CA2723431C - Nip thiazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 - Google Patents
Nip thiazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 Download PDFInfo
- Publication number
- CA2723431C CA2723431C CA2723431A CA2723431A CA2723431C CA 2723431 C CA2723431 C CA 2723431C CA 2723431 A CA2723431 A CA 2723431A CA 2723431 A CA2723431 A CA 2723431A CA 2723431 C CA2723431 C CA 2723431C
- Authority
- CA
- Canada
- Prior art keywords
- piperidin
- thiazol
- carboxylic acid
- octahydro
- cyclopropyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000007979 thiazole derivatives Chemical class 0.000 title claims abstract description 22
- 239000003112 inhibitor Substances 0.000 title description 53
- 102100036506 11-beta-hydroxysteroid dehydrogenase 1 Human genes 0.000 title description 2
- 101710186107 11-beta-hydroxysteroid dehydrogenase 1 Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 166
- 238000011282 treatment Methods 0.000 claims abstract description 43
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 33
- 208000035475 disorder Diseases 0.000 claims abstract description 23
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 21
- 206010020772 Hypertension Diseases 0.000 claims abstract description 16
- 206010022489 Insulin Resistance Diseases 0.000 claims abstract description 16
- 208000008589 Obesity Diseases 0.000 claims abstract description 15
- 235000020824 obesity Nutrition 0.000 claims abstract description 14
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 12
- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 10
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 10
- 208000010877 cognitive disease Diseases 0.000 claims abstract description 9
- 150000002632 lipids Chemical class 0.000 claims abstract description 8
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 6
- 208000010412 Glaucoma Diseases 0.000 claims abstract description 6
- 230000036506 anxiety Effects 0.000 claims abstract description 6
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 5
- 208000026278 immune system disease Diseases 0.000 claims abstract description 4
- -1 2-[1 -(4-Fluoro-benzenesulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic Chemical compound 0.000 claims description 107
- MCQSVVAOVRESQK-UHFFFAOYSA-N n-cyclopropylcyclohexanamine Chemical compound C1CC1NC1CCCCC1 MCQSVVAOVRESQK-UHFFFAOYSA-N 0.000 claims description 70
- 150000003839 salts Chemical class 0.000 claims description 47
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 40
- 239000003814 drug Substances 0.000 claims description 29
- 239000003862 glucocorticoid Substances 0.000 claims description 28
- 229960000890 hydrocortisone Drugs 0.000 claims description 20
- 201000001320 Atherosclerosis Diseases 0.000 claims description 18
- 239000013543 active substance Substances 0.000 claims description 14
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 13
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 10
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 10
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 10
- 239000008103 glucose Substances 0.000 claims description 10
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 10
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 9
- 230000001404 mediated effect Effects 0.000 claims description 8
- 230000004770 neurodegeneration Effects 0.000 claims description 7
- 208000028698 Cognitive impairment Diseases 0.000 claims description 6
- 206010033645 Pancreatitis Diseases 0.000 claims description 6
- 208000017442 Retinal disease Diseases 0.000 claims description 6
- 206010038923 Retinopathy Diseases 0.000 claims description 6
- 201000001421 hyperglycemia Diseases 0.000 claims description 6
- 208000017169 kidney disease Diseases 0.000 claims description 6
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 6
- 201000001119 neuropathy Diseases 0.000 claims description 6
- 230000007823 neuropathy Effects 0.000 claims description 6
- 230000004963 pathophysiological condition Effects 0.000 claims description 6
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 230000004962 physiological condition Effects 0.000 claims description 6
- 238000011321 prophylaxis Methods 0.000 claims description 6
- 208000037803 restenosis Diseases 0.000 claims description 6
- 230000002792 vascular Effects 0.000 claims description 6
- 239000000969 carrier Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 206010018429 Glucose tolerance impaired Diseases 0.000 claims description 3
- 206010024229 Leprosy Diseases 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 230000003955 neuronal function Effects 0.000 claims description 3
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 3
- 201000008827 tuberculosis Diseases 0.000 claims description 3
- 208000001280 Prediabetic State Diseases 0.000 claims description 2
- 230000000644 propagated effect Effects 0.000 claims description 2
- NWLJTRNDQBMUDV-UHFFFAOYSA-N (4-fluorophenyl)-[4-[4-(4-hydroxy-3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]methanone Chemical compound C12CCCCC2C(O)CCN1C(=O)C(N=1)=CSC=1C(CC1)CCN1C(=O)C1=CC=C(F)C=C1 NWLJTRNDQBMUDV-UHFFFAOYSA-N 0.000 claims 1
- XPWAYSYAPJJZOG-UHFFFAOYSA-N (4-hydroxy-3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl)-[2-(1-methylsulfonylpiperidin-4-yl)-1,3-thiazol-4-yl]methanone Chemical compound C1CN(S(=O)(=O)C)CCC1C1=NC(C(=O)N2C3CCCCC3C(O)CC2)=CS1 XPWAYSYAPJJZOG-UHFFFAOYSA-N 0.000 claims 1
- ZFQHRHCKIRAYMM-UHFFFAOYSA-N 1-[4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-2-(4-methoxyphenyl)ethanone Chemical compound C1=CC(OC)=CC=C1CC(=O)N1CCC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CC1 ZFQHRHCKIRAYMM-UHFFFAOYSA-N 0.000 claims 1
- VYGVKAKPUCQPRL-UHFFFAOYSA-N 1-[4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-2-ethylbutan-1-one Chemical compound C1CN(C(=O)C(CC)CC)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 VYGVKAKPUCQPRL-UHFFFAOYSA-N 0.000 claims 1
- BDSZDAAHVJXVQP-UHFFFAOYSA-N 1-[4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-2-methylpropan-1-one Chemical compound C1CN(C(=O)C(C)C)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 BDSZDAAHVJXVQP-UHFFFAOYSA-N 0.000 claims 1
- FBFONVNSQGZZKJ-UHFFFAOYSA-N 1-[4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-2-phenoxyethanone Chemical compound C1CC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CCN1C(=O)COC1=CC=CC=C1 FBFONVNSQGZZKJ-UHFFFAOYSA-N 0.000 claims 1
- QKXKDIAWHUYNER-UHFFFAOYSA-N 1-[4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-2-phenylbutan-1-one Chemical compound C1CC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CCN1C(=O)C(CC)C1=CC=CC=C1 QKXKDIAWHUYNER-UHFFFAOYSA-N 0.000 claims 1
- BQXONXHHJWXYNL-UHFFFAOYSA-N 1-[4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-3,3-dimethylbutan-1-one Chemical compound C1CN(C(=O)CC(C)(C)C)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 BQXONXHHJWXYNL-UHFFFAOYSA-N 0.000 claims 1
- YUNJQSHWFZNSTH-UHFFFAOYSA-N 1-[4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-3-cyclopentylpropan-1-one Chemical compound C1CC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CCN1C(=O)CCC1CCCC1 YUNJQSHWFZNSTH-UHFFFAOYSA-N 0.000 claims 1
- RRQIGXBHFWARNH-UHFFFAOYSA-N 1-[4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-3-methylbutan-1-one Chemical compound C1CN(C(=O)CC(C)C)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 RRQIGXBHFWARNH-UHFFFAOYSA-N 0.000 claims 1
- MIRDCQSJZHXXHL-UHFFFAOYSA-N 1-[4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 MIRDCQSJZHXXHL-UHFFFAOYSA-N 0.000 claims 1
- ZTSWZAMZKSENQO-UHFFFAOYSA-N 1-[4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]pentan-1-one Chemical compound C1CN(C(=O)CCCC)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 ZTSWZAMZKSENQO-UHFFFAOYSA-N 0.000 claims 1
- SHTKOUBAMJYJDM-UHFFFAOYSA-N 1-[4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]propan-1-one Chemical compound C1CN(C(=O)CC)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 SHTKOUBAMJYJDM-UHFFFAOYSA-N 0.000 claims 1
- CQZNBQLHJPYMBR-UHFFFAOYSA-N 1-[4-[4-(4-hydroxy-3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-2-(4-methoxyphenyl)ethanone Chemical compound C1=CC(OC)=CC=C1CC(=O)N1CCC(C=2SC=C(N=2)C(=O)N2C3CCCCC3C(O)CC2)CC1 CQZNBQLHJPYMBR-UHFFFAOYSA-N 0.000 claims 1
- DNJJHCUKDHGAQC-UHFFFAOYSA-N 2-(1-acetylpiperidin-4-yl)-n-cyclohexyl-n-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound C1CN(C(=O)C)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 DNJJHCUKDHGAQC-UHFFFAOYSA-N 0.000 claims 1
- DNESMUNOEGXHTQ-UHFFFAOYSA-N 2-(1-butylsulfonylpiperidin-4-yl)-n-cyclohexyl-n-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound C1CN(S(=O)(=O)CCCC)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 DNESMUNOEGXHTQ-UHFFFAOYSA-N 0.000 claims 1
- DCELNKSXQZPVQH-UHFFFAOYSA-N 2-[1-(2-amino-2-oxoethyl)piperidin-4-yl]-n-cyclohexyl-n-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound C1CN(CC(=O)N)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 DCELNKSXQZPVQH-UHFFFAOYSA-N 0.000 claims 1
- WDDRLMBVJLTUBV-UHFFFAOYSA-N 2-[1-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-n-cyclohexyl-n-methyl-1,3-thiazole-4-carboxamide Chemical compound C=1SC(C2CCN(CC2)S(=O)(=O)C=2C=CC(=CC=2)C(C)(C)C)=NC=1C(=O)N(C)C1CCCCC1 WDDRLMBVJLTUBV-UHFFFAOYSA-N 0.000 claims 1
- LWFAVJCQQLQHBG-UHFFFAOYSA-N 2-[1-(butan-2-ylcarbamoyl)piperidin-4-yl]-n-cyclohexyl-n-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound C1CN(C(=O)NC(C)CC)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 LWFAVJCQQLQHBG-UHFFFAOYSA-N 0.000 claims 1
- AEORGMRUYYPTMV-UHFFFAOYSA-N 2-[1-(cyanomethyl)piperidin-4-yl]-n-cyclohexyl-n-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound C=1SC(C2CCN(CC#N)CC2)=NC=1C(=O)N(C1CCCCC1)C1CC1 AEORGMRUYYPTMV-UHFFFAOYSA-N 0.000 claims 1
- HBEDEXPLRRRXAF-UHFFFAOYSA-N 2-[1-(cyclobutanecarbonyl)piperidin-4-yl]-n-cyclohexyl-n-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound C1CC(C=2SC=C(N=2)C(=O)N(C2CC2)C2CCCCC2)CCN1C(=O)C1CCC1 HBEDEXPLRRRXAF-UHFFFAOYSA-N 0.000 claims 1
- DOHDPSHOOPLJKI-UHFFFAOYSA-N 2-[1-(cyclohexanecarbonyl)piperidin-4-yl]-n-cyclohexyl-n-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound C1CC(C=2SC=C(N=2)C(=O)N(C2CC2)C2CCCCC2)CCN1C(=O)C1CCCCC1 DOHDPSHOOPLJKI-UHFFFAOYSA-N 0.000 claims 1
- XCGXGVUKJHLKIK-UHFFFAOYSA-N 2-[1-(tert-butylcarbamoyl)piperidin-4-yl]-n-cyclohexyl-n-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound C1CN(C(=O)NC(C)(C)C)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 XCGXGVUKJHLKIK-UHFFFAOYSA-N 0.000 claims 1
- VBVIWOFCOOOQHJ-UHFFFAOYSA-N 2-[1-[(4-butylphenyl)carbamoyl]piperidin-4-yl]-n-cyclohexyl-n-methyl-1,3-thiazole-4-carboxamide Chemical compound C1=CC(CCCC)=CC=C1NC(=O)N1CCC(C=2SC=C(N=2)C(=O)N(C)C2CCCCC2)CC1 VBVIWOFCOOOQHJ-UHFFFAOYSA-N 0.000 claims 1
- ZDTJGHRWVLVYLB-UHFFFAOYSA-N 2-[4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]acetonitrile Chemical compound C1CCC2CCCCC2N1C(=O)C(N=1)=CSC=1C1CCN(CC#N)CC1 ZDTJGHRWVLVYLB-UHFFFAOYSA-N 0.000 claims 1
- DCJFVXNAZXQZAY-UHFFFAOYSA-N 3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl-[2-(1-ethylsulfonylpiperidin-4-yl)-1,3-thiazol-4-yl]methanone Chemical compound C1CN(S(=O)(=O)CC)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 DCJFVXNAZXQZAY-UHFFFAOYSA-N 0.000 claims 1
- QZKNFLPYQAYENT-UHFFFAOYSA-N 3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl-[2-(1-methylsulfonylpiperidin-4-yl)-1,3-thiazol-4-yl]methanone Chemical compound C1CN(S(=O)(=O)C)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 QZKNFLPYQAYENT-UHFFFAOYSA-N 0.000 claims 1
- GOMZCHQVMKVYSB-UHFFFAOYSA-N 3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl-[2-(1-pentylpiperidin-4-yl)-1,3-thiazol-4-yl]methanone Chemical compound C1CN(CCCCC)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 GOMZCHQVMKVYSB-UHFFFAOYSA-N 0.000 claims 1
- BTHBYQWWYHIEFU-UHFFFAOYSA-N 3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl-[2-(1-thiophen-2-ylsulfonylpiperidin-4-yl)-1,3-thiazol-4-yl]methanone Chemical compound C1CCC2CCCCC2N1C(=O)C(N=1)=CSC=1C(CC1)CCN1S(=O)(=O)C1=CC=CS1 BTHBYQWWYHIEFU-UHFFFAOYSA-N 0.000 claims 1
- ABSAKJDIZVBYOH-UHFFFAOYSA-N 3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl-[2-[1-(2-methylpropyl)piperidin-4-yl]-1,3-thiazol-4-yl]methanone Chemical compound C1CN(CC(C)C)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 ABSAKJDIZVBYOH-UHFFFAOYSA-N 0.000 claims 1
- PACUUHNWXXCKOI-UHFFFAOYSA-N 3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl-[2-[1-(4-fluorophenyl)sulfonylpiperidin-4-yl]-1,3-thiazol-4-yl]methanone Chemical compound C1=CC(F)=CC=C1S(=O)(=O)N1CCC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CC1 PACUUHNWXXCKOI-UHFFFAOYSA-N 0.000 claims 1
- CCBSQHAKOODGOT-UHFFFAOYSA-N 3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl-[2-[1-(4-methoxyphenyl)sulfonylpiperidin-4-yl]-1,3-thiazol-4-yl]methanone Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N1CCC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CC1 CCBSQHAKOODGOT-UHFFFAOYSA-N 0.000 claims 1
- LGESFOVLTBSGKS-UHFFFAOYSA-N 3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl-[2-[1-(4-tert-butylphenyl)sulfonylpiperidin-4-yl]-1,3-thiazol-4-yl]methanone Chemical compound C1=CC(C(C)(C)C)=CC=C1S(=O)(=O)N1CCC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CC1 LGESFOVLTBSGKS-UHFFFAOYSA-N 0.000 claims 1
- TXMRHEIMAWGRAE-UHFFFAOYSA-N 3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl-[2-[1-(cyclohexylmethyl)piperidin-4-yl]-1,3-thiazol-4-yl]methanone Chemical compound C1CCC2CCCCC2N1C(=O)C(N=1)=CSC=1C(CC1)CCN1CC1CCCCC1 TXMRHEIMAWGRAE-UHFFFAOYSA-N 0.000 claims 1
- ZSNXLSFHAQDCDZ-UHFFFAOYSA-N 3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl-[2-[1-(oxan-2-ylmethyl)piperidin-4-yl]-1,3-thiazol-4-yl]methanone Chemical compound C1CCC2CCCCC2N1C(=O)C(N=1)=CSC=1C(CC1)CCN1CC1CCCCO1 ZSNXLSFHAQDCDZ-UHFFFAOYSA-N 0.000 claims 1
- JZBMTBFKPQRIRL-UHFFFAOYSA-N 3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl-[2-[1-(trifluoromethylsulfonyl)piperidin-4-yl]-1,3-thiazol-4-yl]methanone Chemical compound C1CN(S(=O)(=O)C(F)(F)F)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 JZBMTBFKPQRIRL-UHFFFAOYSA-N 0.000 claims 1
- KOIDYMSVDPGIHT-UHFFFAOYSA-N 3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl-[2-[1-[4-(trifluoromethoxy)phenyl]sulfonylpiperidin-4-yl]-1,3-thiazol-4-yl]methanone Chemical compound C1=CC(OC(F)(F)F)=CC=C1S(=O)(=O)N1CCC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CC1 KOIDYMSVDPGIHT-UHFFFAOYSA-N 0.000 claims 1
- KQPWLCYBFLRCER-UHFFFAOYSA-N 3-[[4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidine-1-carbonyl]amino]propanoic acid Chemical compound C1CN(C(=O)NCCC(=O)O)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 KQPWLCYBFLRCER-UHFFFAOYSA-N 0.000 claims 1
- LAIRGSDOQXIZEW-UHFFFAOYSA-N 3-[[4-[4-[cyclohexyl(methyl)carbamoyl]-1,3-thiazol-2-yl]piperidine-1-carbonyl]amino]propanoic acid Chemical compound C=1SC(C2CCN(CC2)C(=O)NCCC(O)=O)=NC=1C(=O)N(C)C1CCCCC1 LAIRGSDOQXIZEW-UHFFFAOYSA-N 0.000 claims 1
- SVALULYRLWHDIR-UHFFFAOYSA-N 4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]-n-[(4-methoxyphenyl)methyl]piperidine-1-carboxamide Chemical compound C1=CC(OC)=CC=C1CNC(=O)N1CCC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CC1 SVALULYRLWHDIR-UHFFFAOYSA-N 0.000 claims 1
- GSJRMFOVFIWUIM-UHFFFAOYSA-N 4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]-n-butan-2-ylpiperidine-1-carboxamide Chemical compound C1CN(C(=O)NC(C)CC)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 GSJRMFOVFIWUIM-UHFFFAOYSA-N 0.000 claims 1
- BUDXIHRTTHMQDD-UHFFFAOYSA-N 4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]-n-cyclopentylpiperidine-1-carboxamide Chemical compound C1CC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CCN1C(=O)NC1CCCC1 BUDXIHRTTHMQDD-UHFFFAOYSA-N 0.000 claims 1
- VOQPFCRMRFZPQW-UHFFFAOYSA-N 4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]-n-ethylpiperidine-1-carboxamide Chemical compound C1CN(C(=O)NCC)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 VOQPFCRMRFZPQW-UHFFFAOYSA-N 0.000 claims 1
- SBAJZGCZPNUIAU-UHFFFAOYSA-N 4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]-n-pentylpiperidine-1-carboxamide Chemical compound C1CN(C(=O)NCCCCC)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 SBAJZGCZPNUIAU-UHFFFAOYSA-N 0.000 claims 1
- FTLJSDWQAVGUFR-UHFFFAOYSA-N 4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]-n-propan-2-ylpiperidine-1-carboxamide Chemical compound C1CN(C(=O)NC(C)C)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 FTLJSDWQAVGUFR-UHFFFAOYSA-N 0.000 claims 1
- YZWCFEVUNJMUIE-UHFFFAOYSA-N 4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]-n-propylpiperidine-1-carboxamide Chemical compound C1CN(C(=O)NCCC)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 YZWCFEVUNJMUIE-UHFFFAOYSA-N 0.000 claims 1
- GWVYRSVEIFAXJF-UHFFFAOYSA-N 4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]-n-tert-butylpiperidine-1-carboxamide Chemical compound C1CN(C(=O)NC(C)(C)C)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 GWVYRSVEIFAXJF-UHFFFAOYSA-N 0.000 claims 1
- PCVNBERATKXZAC-UHFFFAOYSA-N 4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 PCVNBERATKXZAC-UHFFFAOYSA-N 0.000 claims 1
- NDGBSYHWBBWIHS-UHFFFAOYSA-N 4-[4-(4-hydroxy-3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]-n-[(4-methoxyphenyl)methyl]piperidine-1-carboxamide Chemical compound C1=CC(OC)=CC=C1CNC(=O)N1CCC(C=2SC=C(N=2)C(=O)N2C3CCCCC3C(O)CC2)CC1 NDGBSYHWBBWIHS-UHFFFAOYSA-N 0.000 claims 1
- OLXXYFWQTJOCAE-UHFFFAOYSA-N 4-[4-(4-hydroxy-3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidine-1-carboxylic acid Chemical compound C12CCCCC2C(O)CCN1C(=O)C(N=1)=CSC=1C1CCN(C(O)=O)CC1 OLXXYFWQTJOCAE-UHFFFAOYSA-N 0.000 claims 1
- CEZAIWXFJSUZSC-UHFFFAOYSA-N 4-[4-[cyclohexyl(cyclopropyl)carbamoyl]-1,3-thiazol-2-yl]piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 CEZAIWXFJSUZSC-UHFFFAOYSA-N 0.000 claims 1
- DJBDAJSNNWHYHP-UHFFFAOYSA-N [2-[1-(4-fluorophenyl)sulfonylpiperidin-4-yl]-1,3-thiazol-4-yl]-(4-hydroxy-3,4,4a,5,6,7,8,8a-octahydro-2h-quinolin-1-yl)methanone Chemical compound C12CCCCC2C(O)CCN1C(=O)C(N=1)=CSC=1C(CC1)CCN1S(=O)(=O)C1=CC=C(F)C=C1 DJBDAJSNNWHYHP-UHFFFAOYSA-N 0.000 claims 1
- PDSUQUPFEPWPHQ-UHFFFAOYSA-N [4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-(4-fluorophenyl)methanone Chemical compound C1=CC(F)=CC=C1C(=O)N1CCC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CC1 PDSUQUPFEPWPHQ-UHFFFAOYSA-N 0.000 claims 1
- IIVCKYMFSSJPQN-UHFFFAOYSA-N [4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-[4-(trifluoromethoxy)phenyl]methanone Chemical compound C1=CC(OC(F)(F)F)=CC=C1C(=O)N1CCC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CC1 IIVCKYMFSSJPQN-UHFFFAOYSA-N 0.000 claims 1
- HGCYEDMKFDLYSQ-UHFFFAOYSA-N [4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-cyclobutylmethanone Chemical compound C1CC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CCN1C(=O)C1CCC1 HGCYEDMKFDLYSQ-UHFFFAOYSA-N 0.000 claims 1
- YOOPSZICJCURKK-UHFFFAOYSA-N [4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-cyclohexylmethanone Chemical compound C1CC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CCN1C(=O)C1CCCCC1 YOOPSZICJCURKK-UHFFFAOYSA-N 0.000 claims 1
- JYNIYGGJXZNVJI-UHFFFAOYSA-N [4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-cyclopentylmethanone Chemical compound C1CC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CCN1C(=O)C1CCCC1 JYNIYGGJXZNVJI-UHFFFAOYSA-N 0.000 claims 1
- AMSIUSZDAFVUOE-UHFFFAOYSA-N [4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-cyclopropylmethanone Chemical compound C1CC(C=2SC=C(N=2)C(=O)N2C3CCCCC3CCC2)CCN1C(=O)C1CC1 AMSIUSZDAFVUOE-UHFFFAOYSA-N 0.000 claims 1
- XBEYBPMFQDSZQK-UHFFFAOYSA-N [4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidin-1-yl]-pyridin-3-ylmethanone Chemical compound C1CCC2CCCCC2N1C(=O)C(N=1)=CSC=1C(CC1)CCN1C(=O)C1=CC=CN=C1 XBEYBPMFQDSZQK-UHFFFAOYSA-N 0.000 claims 1
- XVBJJIOMVIADLO-UHFFFAOYSA-N n-cyclohexyl-2-[1-(2-cyclohexylethyl)piperidin-4-yl]-n-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound C=1SC(C2CCN(CCC3CCCCC3)CC2)=NC=1C(=O)N(C1CCCCC1)C1CC1 XVBJJIOMVIADLO-UHFFFAOYSA-N 0.000 claims 1
- VHTUXLFTPGPPTJ-UHFFFAOYSA-N n-cyclohexyl-2-[1-(3-cyclopentylpropanoyl)piperidin-4-yl]-n-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound C1CC(C=2SC=C(N=2)C(=O)N(C2CC2)C2CCCCC2)CCN1C(=O)CCC1CCCC1 VHTUXLFTPGPPTJ-UHFFFAOYSA-N 0.000 claims 1
- FSONLKBZSWJFOJ-UHFFFAOYSA-N n-cyclohexyl-2-[1-(4-methoxyphenyl)sulfonylpiperidin-4-yl]-n-methyl-1,3-thiazole-4-carboxamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N1CCC(C=2SC=C(N=2)C(=O)N(C)C2CCCCC2)CC1 FSONLKBZSWJFOJ-UHFFFAOYSA-N 0.000 claims 1
- WRAAWTXSOYPJNL-UHFFFAOYSA-N n-cyclohexyl-2-[1-(cyclohexylmethyl)piperidin-4-yl]-n-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound C=1SC(C2CCN(CC3CCCCC3)CC2)=NC=1C(=O)N(C1CCCCC1)C1CC1 WRAAWTXSOYPJNL-UHFFFAOYSA-N 0.000 claims 1
- YZVBTDOBGCVVGL-UHFFFAOYSA-N n-cyclohexyl-2-[1-(cyclopentanecarbonyl)piperidin-4-yl]-n-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound C1CC(C=2SC=C(N=2)C(=O)N(C2CC2)C2CCCCC2)CCN1C(=O)C1CCCC1 YZVBTDOBGCVVGL-UHFFFAOYSA-N 0.000 claims 1
- UFOOLNOPWUNIFX-UHFFFAOYSA-N n-cyclohexyl-2-[1-(cyclopentylcarbamoyl)piperidin-4-yl]-n-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound C1CC(C=2SC=C(N=2)C(=O)N(C2CC2)C2CCCCC2)CCN1C(=O)NC1CCCC1 UFOOLNOPWUNIFX-UHFFFAOYSA-N 0.000 claims 1
- JLDFBSJGVGOKIY-UHFFFAOYSA-N n-cyclohexyl-2-[1-(cyclopropanecarbonyl)piperidin-4-yl]-n-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound C1CC(C=2SC=C(N=2)C(=O)N(C2CC2)C2CCCCC2)CCN1C(=O)C1CC1 JLDFBSJGVGOKIY-UHFFFAOYSA-N 0.000 claims 1
- DEWCJOXAVUDBIQ-UHFFFAOYSA-N n-cyclohexyl-2-[1-[(4-methoxyphenyl)methylcarbamoyl]piperidin-4-yl]-n-methyl-1,3-thiazole-4-carboxamide Chemical compound C1=CC(OC)=CC=C1CNC(=O)N1CCC(C=2SC=C(N=2)C(=O)N(C)C2CCCCC2)CC1 DEWCJOXAVUDBIQ-UHFFFAOYSA-N 0.000 claims 1
- BOVMXWXKVOYNEN-UHFFFAOYSA-N n-cyclohexyl-2-[1-[2-(4-methoxyphenyl)acetyl]piperidin-4-yl]-n-methyl-1,3-thiazole-4-carboxamide Chemical compound C1=CC(OC)=CC=C1CC(=O)N1CCC(C=2SC=C(N=2)C(=O)N(C)C2CCCCC2)CC1 BOVMXWXKVOYNEN-UHFFFAOYSA-N 0.000 claims 1
- ZFEBUTPQQGMZMV-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-(1-ethylsulfonylpiperidin-4-yl)-1,3-thiazole-4-carboxamide Chemical compound C1CN(S(=O)(=O)CC)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 ZFEBUTPQQGMZMV-UHFFFAOYSA-N 0.000 claims 1
- VWZKIDGRFYUUKH-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-(1-methylsulfonylpiperidin-4-yl)-1,3-thiazole-4-carboxamide Chemical compound C1CN(S(=O)(=O)C)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 VWZKIDGRFYUUKH-UHFFFAOYSA-N 0.000 claims 1
- MJLLSCZLXAUYRJ-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-(1-pentanoylpiperidin-4-yl)-1,3-thiazole-4-carboxamide Chemical compound C1CN(C(=O)CCCC)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 MJLLSCZLXAUYRJ-UHFFFAOYSA-N 0.000 claims 1
- WPLVQPPXBKWSDC-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-(1-pentylpiperidin-4-yl)-1,3-thiazole-4-carboxamide Chemical compound C1CN(CCCCC)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 WPLVQPPXBKWSDC-UHFFFAOYSA-N 0.000 claims 1
- MTVXNXUEZZCSOF-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-(1-propan-2-ylsulfonylpiperidin-4-yl)-1,3-thiazole-4-carboxamide Chemical compound C1CN(S(=O)(=O)C(C)C)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 MTVXNXUEZZCSOF-UHFFFAOYSA-N 0.000 claims 1
- GWJJDGBNPSJLEL-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-(1-propanoylpiperidin-4-yl)-1,3-thiazole-4-carboxamide Chemical compound C1CN(C(=O)CC)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 GWJJDGBNPSJLEL-UHFFFAOYSA-N 0.000 claims 1
- BBDIAXLEWILNNH-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-(1-propylsulfonylpiperidin-4-yl)-1,3-thiazole-4-carboxamide Chemical compound C1CN(S(=O)(=O)CCC)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 BBDIAXLEWILNNH-UHFFFAOYSA-N 0.000 claims 1
- LBNPUSMEFQRZJH-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-(1-thiophen-2-ylsulfonylpiperidin-4-yl)-1,3-thiazole-4-carboxamide Chemical compound C=1SC(C2CCN(CC2)S(=O)(=O)C=2SC=CC=2)=NC=1C(=O)N(C1CCCCC1)C1CC1 LBNPUSMEFQRZJH-UHFFFAOYSA-N 0.000 claims 1
- BHTFOMZTXCFPQB-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(2-ethylbutanoyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1CN(C(=O)C(CC)CC)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 BHTFOMZTXCFPQB-UHFFFAOYSA-N 0.000 claims 1
- HNPALPWHIATTJT-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(2-methylpropyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1CN(CC(C)C)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 HNPALPWHIATTJT-UHFFFAOYSA-N 0.000 claims 1
- BCDIKGDLEZUIQO-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(2-phenoxyacetyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1CC(C=2SC=C(N=2)C(=O)N(C2CC2)C2CCCCC2)CCN1C(=O)COC1=CC=CC=C1 BCDIKGDLEZUIQO-UHFFFAOYSA-N 0.000 claims 1
- RLUGBVXTUKQZBT-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(2-phenylbutanoyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C=1C=CC=CC=1C(CC)C(=O)N(CC1)CCC1C(SC=1)=NC=1C(=O)N(C1CCCCC1)C1CC1 RLUGBVXTUKQZBT-UHFFFAOYSA-N 0.000 claims 1
- OTIWUAYMSQNJOT-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(2-pyridin-4-ylethylsulfonyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C=1SC(C2CCN(CC2)S(=O)(=O)CCC=2C=CN=CC=2)=NC=1C(=O)N(C1CCCCC1)C1CC1 OTIWUAYMSQNJOT-UHFFFAOYSA-N 0.000 claims 1
- YXTYTSMMHZSOPJ-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(3,3-dimethylbutanoyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1CN(C(=O)CC(C)(C)C)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 YXTYTSMMHZSOPJ-UHFFFAOYSA-N 0.000 claims 1
- KBLOJAQCRXDCOO-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(3-methylbutanoyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1CN(C(=O)CC(C)C)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 KBLOJAQCRXDCOO-UHFFFAOYSA-N 0.000 claims 1
- ZAGBMSKUTVLIQT-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(3-methylbutyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1CN(CCC(C)C)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 ZAGBMSKUTVLIQT-UHFFFAOYSA-N 0.000 claims 1
- RTTGMLHVJYYTKJ-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(ethylcarbamoyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1CN(C(=O)NCC)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 RTTGMLHVJYYTKJ-UHFFFAOYSA-N 0.000 claims 1
- QHZKRFXIXCEKLQ-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(oxan-2-ylmethyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C=1SC(C2CCN(CC3OCCCC3)CC2)=NC=1C(=O)N(C1CCCCC1)C1CC1 QHZKRFXIXCEKLQ-UHFFFAOYSA-N 0.000 claims 1
- CFPSBZBKFBFUAD-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(pentylcarbamoyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1CN(C(=O)NCCCCC)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 CFPSBZBKFBFUAD-UHFFFAOYSA-N 0.000 claims 1
- FBSRGODYTGHMMH-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(propan-2-ylcarbamoyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1CN(C(=O)NC(C)C)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 FBSRGODYTGHMMH-UHFFFAOYSA-N 0.000 claims 1
- FOFGWOPOTFTISP-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(propylcarbamoyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1CN(C(=O)NCCC)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 FOFGWOPOTFTISP-UHFFFAOYSA-N 0.000 claims 1
- KIGWINDEJQFSQL-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(pyridine-3-carbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C=1SC(C2CCN(CC2)C(=O)C=2C=NC=CC=2)=NC=1C(=O)N(C1CCCCC1)C1CC1 KIGWINDEJQFSQL-UHFFFAOYSA-N 0.000 claims 1
- VHTOOKPMBPQWFQ-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-(trifluoromethylsulfonyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1CN(S(=O)(=O)C(F)(F)F)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 VHTOOKPMBPQWFQ-UHFFFAOYSA-N 0.000 claims 1
- XOXISVRQDPFWHH-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-[(4-methoxyphenyl)methylcarbamoyl]piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1=CC(OC)=CC=C1CNC(=O)N1CCC(C=2SC=C(N=2)C(=O)N(C2CC2)C2CCCCC2)CC1 XOXISVRQDPFWHH-UHFFFAOYSA-N 0.000 claims 1
- YOCCZMFCMJONNK-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-[2-(4-methoxyphenyl)acetyl]piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1=CC(OC)=CC=C1CC(=O)N1CCC(C=2SC=C(N=2)C(=O)N(C2CC2)C2CCCCC2)CC1 YOCCZMFCMJONNK-UHFFFAOYSA-N 0.000 claims 1
- NPSMAHHLCQHFPU-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-[4-(trifluoromethoxy)benzoyl]piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1C(=O)N1CCC(C=2SC=C(N=2)C(=O)N(C2CC2)C2CCCCC2)CC1 NPSMAHHLCQHFPU-UHFFFAOYSA-N 0.000 claims 1
- ZZFDMWDTIITLOR-UHFFFAOYSA-N n-cyclohexyl-n-cyclopropyl-2-[1-[4-(trifluoromethoxy)phenyl]sulfonylpiperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1S(=O)(=O)N1CCC(C=2SC=C(N=2)C(=O)N(C2CC2)C2CCCCC2)CC1 ZZFDMWDTIITLOR-UHFFFAOYSA-N 0.000 claims 1
- SXCKBRCEWBDQLH-UHFFFAOYSA-N n-cyclohexyl-n-methyl-2-(1-methylsulfonylpiperidin-4-yl)-1,3-thiazole-4-carboxamide Chemical compound C=1SC(C2CCN(CC2)S(C)(=O)=O)=NC=1C(=O)N(C)C1CCCCC1 SXCKBRCEWBDQLH-UHFFFAOYSA-N 0.000 claims 1
- RBUXVQSXHHWEEZ-UHFFFAOYSA-N n-cyclohexyl-n-methyl-2-[1-(2-phenoxyacetyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C=1SC(C2CCN(CC2)C(=O)COC=2C=CC=CC=2)=NC=1C(=O)N(C)C1CCCCC1 RBUXVQSXHHWEEZ-UHFFFAOYSA-N 0.000 claims 1
- SWSJVMUIGGKRRN-UHFFFAOYSA-N n-cyclohexyl-n-methyl-2-[1-(2-phenylbutanoyl)piperidin-4-yl]-1,3-thiazole-4-carboxamide Chemical compound C=1C=CC=CC=1C(CC)C(=O)N(CC1)CCC1C(SC=1)=NC=1C(=O)N(C)C1CCCCC1 SWSJVMUIGGKRRN-UHFFFAOYSA-N 0.000 claims 1
- DDRANYVBKPEUAF-UHFFFAOYSA-N tert-butyl 4-[4-(3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C(=O)N2C3CCCCC3CCC2)=CS1 DDRANYVBKPEUAF-UHFFFAOYSA-N 0.000 claims 1
- DTJJSFYVXOLKQF-UHFFFAOYSA-N tert-butyl 4-[4-(4-hydroxy-3,4,4a,5,6,7,8,8a-octahydro-2h-quinoline-1-carbonyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C(=O)N2C3CCCCC3C(O)CC2)=CS1 DTJJSFYVXOLKQF-UHFFFAOYSA-N 0.000 claims 1
- KYKLSUVROVSNSL-UHFFFAOYSA-N tert-butyl 4-[4-[cyclohexyl(cyclopropyl)carbamoyl]-1,3-thiazol-2-yl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC(C(=O)N(C2CC2)C2CCCCC2)=CS1 KYKLSUVROVSNSL-UHFFFAOYSA-N 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 10
- 230000002265 prevention Effects 0.000 abstract description 9
- 102000008645 11-beta-Hydroxysteroid Dehydrogenase Type 1 Human genes 0.000 abstract description 4
- 108010088011 11-beta-Hydroxysteroid Dehydrogenase Type 1 Proteins 0.000 abstract description 4
- 229940124639 Selective inhibitor Drugs 0.000 abstract description 4
- 238000000034 method Methods 0.000 description 42
- 239000000203 mixture Substances 0.000 description 39
- 235000013350 formula milk Nutrition 0.000 description 37
- 125000003118 aryl group Chemical group 0.000 description 33
- 230000005764 inhibitory process Effects 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 28
- 125000000217 alkyl group Chemical group 0.000 description 26
- 230000000694 effects Effects 0.000 description 25
- 239000002253 acid Substances 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 23
- 239000012453 solvate Substances 0.000 description 21
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 20
- 125000001424 substituent group Chemical group 0.000 description 20
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 19
- 229940002612 prodrug Drugs 0.000 description 19
- 239000000651 prodrug Substances 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- 125000000753 cycloalkyl group Chemical group 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000000556 agonist Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 125000001072 heteroaryl group Chemical group 0.000 description 15
- 241000282414 Homo sapiens Species 0.000 description 14
- 239000004480 active ingredient Substances 0.000 description 14
- 229910052736 halogen Inorganic materials 0.000 description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- 150000002367 halogens Chemical class 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 229940037128 systemic glucocorticoids Drugs 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000007792 addition Methods 0.000 description 12
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 12
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
- 102000004877 Insulin Human genes 0.000 description 10
- 108090001061 Insulin Proteins 0.000 description 10
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 239000002775 capsule Substances 0.000 description 10
- 229940125396 insulin Drugs 0.000 description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 150000003254 radicals Chemical class 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 9
- 210000004556 brain Anatomy 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 229960001031 glucose Drugs 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 125000004430 oxygen atom Chemical group O* 0.000 description 9
- 230000009467 reduction Effects 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 125000004104 aryloxy group Chemical group 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 230000000875 corresponding effect Effects 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 8
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 7
- OGIQUQKNJJTLSZ-UHFFFAOYSA-N 4-butylaniline Chemical compound CCCCC1=CC=C(N)C=C1 OGIQUQKNJJTLSZ-UHFFFAOYSA-N 0.000 description 7
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 7
- 229920002472 Starch Polymers 0.000 description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000000306 component Substances 0.000 description 7
- 125000001207 fluorophenyl group Chemical group 0.000 description 7
- 229920000159 gelatin Polymers 0.000 description 7
- 235000019322 gelatine Nutrition 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000000829 suppository Substances 0.000 description 7
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 description 7
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 7
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 6
- 208000004611 Abdominal Obesity Diseases 0.000 description 6
- 206010065941 Central obesity Diseases 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- 239000001828 Gelatine Substances 0.000 description 6
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 6
- 102000002072 Non-Receptor Type 1 Protein Tyrosine Phosphatase Human genes 0.000 description 6
- 108010015847 Non-Receptor Type 1 Protein Tyrosine Phosphatase Proteins 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- 102000002808 Pituitary adenylate cyclase-activating polypeptide Human genes 0.000 description 6
- 108010004684 Pituitary adenylate cyclase-activating polypeptide Proteins 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 6
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 230000003579 anti-obesity Effects 0.000 description 6
- 230000009286 beneficial effect Effects 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 235000001727 glucose Nutrition 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 210000004185 liver Anatomy 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 229960005419 nitrogen Drugs 0.000 description 6
- 239000002798 polar solvent Substances 0.000 description 6
- 229940044601 receptor agonist Drugs 0.000 description 6
- 239000000018 receptor agonist Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 5
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 5
- 102000011145 Hydroxysteroid Dehydrogenases Human genes 0.000 description 5
- 108010062875 Hydroxysteroid Dehydrogenases Proteins 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000006071 cream Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 229960004756 ethanol Drugs 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 238000004949 mass spectrometry Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 238000007911 parenteral administration Methods 0.000 description 5
- 235000011007 phosphoric acid Nutrition 0.000 description 5
- 125000003367 polycyclic group Polymers 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 229940093956 potassium carbonate Drugs 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 235000012222 talc Nutrition 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 229940123208 Biguanide Drugs 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 108010061846 Cholesterol Ester Transfer Proteins Proteins 0.000 description 4
- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 description 4
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 4
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 4
- 102400001132 Melanin-concentrating hormone Human genes 0.000 description 4
- 101800002739 Melanin-concentrating hormone Proteins 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- TUEGIDNKMDJKSP-UHFFFAOYSA-N N-cyclohexyl-N-cyclopropyl-1,3-thiazole-4-carboxamide Chemical compound O=C(N(C1CC1)C1CCCCC1)c1cscn1 TUEGIDNKMDJKSP-UHFFFAOYSA-N 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- 101150014691 PPARA gene Proteins 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229940100389 Sulfonylurea Drugs 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 125000003710 aryl alkyl group Chemical group 0.000 description 4
- 150000004283 biguanides Chemical class 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 229960004544 cortisone Drugs 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical class CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 230000002440 hepatic effect Effects 0.000 description 4
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 4
- 229940090044 injection Drugs 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- ORRDHOMWDPJSNL-UHFFFAOYSA-N melanin concentrating hormone Chemical compound N1C(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC(=O)C(C(C)C)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(CCCNC(N)=N)NC(=O)C(NC(=O)C(NC(=O)C(N)CC(O)=O)C(C)O)CCSC)CSSCC(C(=O)NC(CC=2C3=CC=CC=C3NC=2)C(=O)NC(CCC(O)=O)C(=O)NC(C(C)C)C(O)=O)NC(=O)C2CCCN2C(=O)C(CCCNC(N)=N)NC(=O)C1CC1=CC=C(O)C=C1 ORRDHOMWDPJSNL-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 239000011664 nicotinic acid Substances 0.000 description 4
- 229960003512 nicotinic acid Drugs 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- DHHVAGZRUROJKS-UHFFFAOYSA-N phentermine Chemical compound CC(C)(N)CC1=CC=CC=C1 DHHVAGZRUROJKS-UHFFFAOYSA-N 0.000 description 4
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229960002855 simvastatin Drugs 0.000 description 4
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 4
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 4
- 150000003557 thiazoles Chemical class 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 3
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 3
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 3
- MVQVNTPHUGQQHK-UHFFFAOYSA-N 3-pyridinemethanol Chemical compound OCC1=CC=CN=C1 MVQVNTPHUGQQHK-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 239000005541 ACE inhibitor Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 108010064733 Angiotensins Proteins 0.000 description 3
- 102000015427 Angiotensins Human genes 0.000 description 3
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 3
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 239000002083 C09CA01 - Losartan Substances 0.000 description 3
- 239000002080 C09CA02 - Eprosartan Substances 0.000 description 3
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 3
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 3
- 239000002081 C09CA05 - Tasosartan Substances 0.000 description 3
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 3
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 108010061435 Enalapril Proteins 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 3
- 229940122904 Glucagon receptor antagonist Drugs 0.000 description 3
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 description 3
- 102000003638 Glucose-6-Phosphatase Human genes 0.000 description 3
- 108010086800 Glucose-6-Phosphatase Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 229940122199 Insulin secretagogue Drugs 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 108010007859 Lisinopril Proteins 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 102000003797 Neuropeptides Human genes 0.000 description 3
- 108090000189 Neuropeptides Proteins 0.000 description 3
- 102000014743 Pituitary Adenylate Cyclase-Activating Polypeptide Receptors Human genes 0.000 description 3
- 108010064032 Pituitary Adenylate Cyclase-Activating Polypeptide Receptors Proteins 0.000 description 3
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 3
- 102100040918 Pro-glucagon Human genes 0.000 description 3
- 108090000783 Renin Proteins 0.000 description 3
- 102100028255 Renin Human genes 0.000 description 3
- 235000021355 Stearic acid Nutrition 0.000 description 3
- 102000001494 Sterol O-Acyltransferase Human genes 0.000 description 3
- 108010054082 Sterol O-acyltransferase Proteins 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 102000008316 Type 4 Melanocortin Receptor Human genes 0.000 description 3
- 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 239000002404 acyltransferase inhibitor Substances 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 3
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 3
- 239000003529 anticholesteremic agent Substances 0.000 description 3
- 229940127226 anticholesterol agent Drugs 0.000 description 3
- 239000002220 antihypertensive agent Substances 0.000 description 3
- 229940030600 antihypertensive agent Drugs 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 150000005840 aryl radicals Chemical class 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 229960005370 atorvastatin Drugs 0.000 description 3
- 210000000988 bone and bone Anatomy 0.000 description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 3
- 229960000932 candesartan Drugs 0.000 description 3
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 3
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 3
- 229960000830 captopril Drugs 0.000 description 3
- OBZHEBDUNPOCJG-SZTGPWMUSA-N carbenoxolone Chemical compound C([C@H]1C2=CC(=O)[C@@H]34)[C@](C)(C(O)=O)CC[C@@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@H]1[C@@]3(C)CC[C@@H](OC(=O)CCC(O)=O)C1(C)C OBZHEBDUNPOCJG-SZTGPWMUSA-N 0.000 description 3
- 229960000530 carbenoxolone Drugs 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 229960005110 cerivastatin Drugs 0.000 description 3
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 230000001906 cholesterol absorption Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 description 3
- 229960005025 cilazapril Drugs 0.000 description 3
- 229950006523 cilexetil Drugs 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- VTDCYOLLYVAJSY-UHFFFAOYSA-N cyclohexyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OC1CCCCC1 VTDCYOLLYVAJSY-UHFFFAOYSA-N 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- HWDVTQAXQJQROO-UHFFFAOYSA-N cyclopropylazanide Chemical compound [NH-]C1CC1 HWDVTQAXQJQROO-UHFFFAOYSA-N 0.000 description 3
- 230000009977 dual effect Effects 0.000 description 3
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 3
- 229960000873 enalapril Drugs 0.000 description 3
- 229960004563 eprosartan Drugs 0.000 description 3
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 description 3
- 229960003765 fluvastatin Drugs 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 235000012631 food intake Nutrition 0.000 description 3
- 229960002490 fosinopril Drugs 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 108010036598 gastric inhibitory polypeptide receptor Proteins 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 230000009229 glucose formation Effects 0.000 description 3
- 230000008348 humoral response Effects 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 229960000443 hydrochloric acid Drugs 0.000 description 3
- 230000028993 immune response Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 229960002198 irbesartan Drugs 0.000 description 3
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229960002394 lisinopril Drugs 0.000 description 3
- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 3
- 229960004773 losartan Drugs 0.000 description 3
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 3
- 229960004844 lovastatin Drugs 0.000 description 3
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 3
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- 239000000336 melanocortin receptor agonist Substances 0.000 description 3
- 239000002207 metabolite Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- WJLHMHZSRLDMCA-UHFFFAOYSA-N n-(4-butylphenyl)piperidine-1-carboxamide Chemical compound C1=CC(CCCC)=CC=C1NC(=O)N1CCCCC1 WJLHMHZSRLDMCA-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 235000001968 nicotinic acid Nutrition 0.000 description 3
- 229960004738 nicotinyl alcohol Drugs 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229960002797 pitavastatin Drugs 0.000 description 3
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 229960002965 pravastatin Drugs 0.000 description 3
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000003380 propellant Substances 0.000 description 3
- JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 description 3
- 229960001455 quinapril Drugs 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000002464 receptor antagonist Substances 0.000 description 3
- 239000002461 renin inhibitor Substances 0.000 description 3
- 229940086526 renin-inhibitors Drugs 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 229960000672 rosuvastatin Drugs 0.000 description 3
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 3
- 230000001235 sensitizing effect Effects 0.000 description 3
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 230000035882 stress Effects 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 229960000651 tasosartan Drugs 0.000 description 3
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- 229960004699 valsartan Drugs 0.000 description 3
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 3
- 229960002769 zofenopril Drugs 0.000 description 3
- IAIDUHCBNLFXEF-MNEFBYGVSA-N zofenopril Chemical compound C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C(O)=O)SC(=O)C1=CC=CC=C1 IAIDUHCBNLFXEF-MNEFBYGVSA-N 0.000 description 3
- DBGIVFWFUFKIQN-UHFFFAOYSA-N (+-)-Fenfluramine Chemical compound CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- FUFLCEKSBBHCMO-KJQYFISQSA-N 11-dehydrocorticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 FUFLCEKSBBHCMO-KJQYFISQSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- JLLYLQLDYORLBB-UHFFFAOYSA-N 5-bromo-n-methylthiophene-2-sulfonamide Chemical compound CNS(=O)(=O)C1=CC=C(Br)S1 JLLYLQLDYORLBB-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 2
- 229940123158 Cannabinoid CB1 receptor antagonist Drugs 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 2
- OMFXVFTZEKFJBZ-UHFFFAOYSA-N Corticosterone Natural products O=C1CCC2(C)C3C(O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 OMFXVFTZEKFJBZ-UHFFFAOYSA-N 0.000 description 2
- 241001274613 Corvus frugilegus Species 0.000 description 2
- 208000014311 Cushing syndrome Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- 101800001586 Ghrelin Proteins 0.000 description 2
- 102400000442 Ghrelin-28 Human genes 0.000 description 2
- 208000002705 Glucose Intolerance Diseases 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001529936 Murinae Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 206010029350 Neurotoxicity Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 235000021314 Palmitic acid Nutrition 0.000 description 2
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 2
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 description 2
- 102100039418 Plasminogen activator inhibitor 1 Human genes 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 206010044221 Toxic encephalopathy Diseases 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229940081735 acetylcellulose Drugs 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 210000001789 adipocyte Anatomy 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- HXXFSFRBOHSIMQ-VFUOTHLCSA-N alpha-D-glucose 1-phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(O)=O)[C@H](O)[C@@H](O)[C@@H]1O HXXFSFRBOHSIMQ-VFUOTHLCSA-N 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 150000003938 benzyl alcohols Chemical class 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229940074995 bromine Drugs 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 229940077731 carbohydrate nutrients Drugs 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 238000005266 casting Methods 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 230000001886 ciliary effect Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000006196 drop Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 238000000132 electrospray ionisation Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000012055 enteric layer Substances 0.000 description 2
- 238000001952 enzyme assay Methods 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 2
- 229960000815 ezetimibe Drugs 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 229960001582 fenfluramine Drugs 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- GNKDKYIHGQKHHM-RJKLHVOGSA-N ghrelin Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CN)COC(=O)CCCCCCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=CC=C1 GNKDKYIHGQKHHM-RJKLHVOGSA-N 0.000 description 2
- 230000004110 gluconeogenesis Effects 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 2
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 229940121380 ileal bile acid transporter inhibitor Drugs 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 230000004410 intraocular pressure Effects 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 150000002513 isocyanates Chemical class 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 229960000448 lactic acid Drugs 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- XUXJHBAJZQREDB-UHFFFAOYSA-N methylbutylamide Natural products CCC(C)C(N)=O XUXJHBAJZQREDB-UHFFFAOYSA-N 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- AWHRFYGGUMKLML-UHFFFAOYSA-N n-[(4-methoxyphenyl)methyl]piperidine-1-carboxamide Chemical compound C1=CC(OC)=CC=C1CNC(=O)N1CCCCC1 AWHRFYGGUMKLML-UHFFFAOYSA-N 0.000 description 2
- XXODVJHJUCLFBY-UHFFFAOYSA-N n-butan-2-ylpiperidine-1-carboxamide Chemical compound CCC(C)NC(=O)N1CCCCC1 XXODVJHJUCLFBY-UHFFFAOYSA-N 0.000 description 2
- CMJDBBWLMFVKSK-UHFFFAOYSA-N n-cyclopentylpiperidine-1-carboxamide Chemical compound C1CCCCN1C(=O)NC1CCCC1 CMJDBBWLMFVKSK-UHFFFAOYSA-N 0.000 description 2
- YJYVXELRDSTYFG-UHFFFAOYSA-N n-ethylpiperidine-1-carboxamide Chemical compound CCNC(=O)N1CCCCC1 YJYVXELRDSTYFG-UHFFFAOYSA-N 0.000 description 2
- BYLSLFMFQJERRE-UHFFFAOYSA-N n-propylpiperidine-1-carboxamide Chemical compound CCCNC(=O)N1CCCCC1 BYLSLFMFQJERRE-UHFFFAOYSA-N 0.000 description 2
- 230000006764 neuronal dysfunction Effects 0.000 description 2
- 230000007135 neurotoxicity Effects 0.000 description 2
- 231100000228 neurotoxicity Toxicity 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 2
- 229960001243 orlistat Drugs 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- 229960003562 phentermine Drugs 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- XUWVIABDWDTJRZ-UHFFFAOYSA-N propan-2-ylazanide Chemical compound CC(C)[NH-] XUWVIABDWDTJRZ-UHFFFAOYSA-N 0.000 description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- BHRZNVHARXXAHW-UHFFFAOYSA-N sec-butylamine Chemical compound CCC(C)N BHRZNVHARXXAHW-UHFFFAOYSA-N 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 229960004425 sibutramine Drugs 0.000 description 2
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- AGGIJOLULBJGTQ-UHFFFAOYSA-N sulfoacetic acid Chemical compound OC(=O)CS(O)(=O)=O AGGIJOLULBJGTQ-UHFFFAOYSA-N 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 229960005187 telmisartan Drugs 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- DBGIVFWFUFKIQN-VIFPVBQESA-N (+)-Fenfluramine Chemical compound CCN[C@@H](C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-VIFPVBQESA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- ZSOPWZQRZHWYFY-NUXPJIRBSA-N (2s,3s)-2-amino-3-methyl-1-(1,3-thiazolidin-3-yl)pentan-1-one;(e)-but-2-enedioic acid Chemical compound OC(=O)\C=C\C(O)=O.CC[C@H](C)[C@H](N)C(=O)N1CCSC1 ZSOPWZQRZHWYFY-NUXPJIRBSA-N 0.000 description 1
- MPDGHEJMBKOTSU-WFJWTYAKSA-N (2s,4as,6as,6br,10s,12as)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylic acid Chemical compound C12C(=O)C=C3C4C[C@@](C)(C(O)=O)CC[C@]4(C)CC[C@@]3(C)[C@]1(C)CCC1[C@]2(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-WFJWTYAKSA-N 0.000 description 1
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 1
- AXJQVVLKUYCICH-OAQYLSRUSA-N (4s)-5-(4-chlorophenyl)-n-(4-chlorophenyl)sulfonyl-n'-methyl-4-phenyl-3,4-dihydropyrazole-2-carboximidamide Chemical compound C=1C=C(Cl)C=CC=1C([C@H](C1)C=2C=CC=CC=2)=NN1C(=NC)NS(=O)(=O)C1=CC=C(Cl)C=C1 AXJQVVLKUYCICH-OAQYLSRUSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006763 (C3-C9) cycloalkyl group Chemical group 0.000 description 1
- MLQARXBFLAEGNM-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinolin-4-ol Chemical compound C1CCCC2C(O)CCNC21 MLQARXBFLAEGNM-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- HMVYYTRDXNKRBQ-UHFFFAOYSA-N 1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=CSC=N1 HMVYYTRDXNKRBQ-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- LJJRXPXDTAUVQU-UHFFFAOYSA-N 1-butyl-4-isocyanatobenzene Chemical compound CCCCC1=CC=C(N=C=O)C=C1 LJJRXPXDTAUVQU-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 102000004277 11-beta-hydroxysteroid dehydrogenases Human genes 0.000 description 1
- 108090000874 11-beta-hydroxysteroid dehydrogenases Proteins 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- HZNQSWJZTWOTKM-UHFFFAOYSA-N 2,3,4-trimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(OC)=C1OC HZNQSWJZTWOTKM-UHFFFAOYSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- QIJIUJYANDSEKG-UHFFFAOYSA-N 2,4,4-trimethylpentan-2-amine Chemical compound CC(C)(C)CC(C)(C)N QIJIUJYANDSEKG-UHFFFAOYSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical group COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- GRWKNBPOGBTZMN-UHFFFAOYSA-N 2-benzyl-3-phenylpropane-1,2-diamine Chemical compound C=1C=CC=CC=1CC(N)(CN)CC1=CC=CC=C1 GRWKNBPOGBTZMN-UHFFFAOYSA-N 0.000 description 1
- HABAPWZXRLIZDL-UHFFFAOYSA-N 2-chloro-2-phenoxyacetic acid Chemical compound OC(=O)C(Cl)OC1=CC=CC=C1 HABAPWZXRLIZDL-UHFFFAOYSA-N 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 1
- WVVJEIQJCDUVSP-UHFFFAOYSA-N 4-carbamothioylpiperidine-1-carboxylic acid Chemical compound NC(=S)C1CCN(C(O)=O)CC1 WVVJEIQJCDUVSP-UHFFFAOYSA-N 0.000 description 1
- NFFXEUUOMTXWCX-UHFFFAOYSA-N 5-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]-2-methoxy-n-[[4-(trifluoromethyl)phenyl]methyl]benzamide Chemical compound C1=C(C(=O)NCC=2C=CC(=CC=2)C(F)(F)F)C(OC)=CC=C1CC1SC(=O)NC1=O NFFXEUUOMTXWCX-UHFFFAOYSA-N 0.000 description 1
- MVDXXGIBARMXSA-PYUWXLGESA-N 5-[[(2r)-2-benzyl-3,4-dihydro-2h-chromen-6-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(O[C@@H](CC=2C=CC=CC=2)CC2)C2=C1 MVDXXGIBARMXSA-PYUWXLGESA-N 0.000 description 1
- VFFZWMWTUSXDCB-ZDUSSCGKSA-N 6-[2-[[2-[(2s)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]amino]ethylamino]pyridine-3-carbonitrile Chemical compound N1([C@@H](CCC1)C#N)C(=O)CNCCNC1=CC=C(C#N)C=N1 VFFZWMWTUSXDCB-ZDUSSCGKSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- PTQXTEKSNBVPQJ-UHFFFAOYSA-N Avasimibe Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1CC(=O)NS(=O)(=O)OC1=C(C(C)C)C=CC=C1C(C)C PTQXTEKSNBVPQJ-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 1
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 1
- MSPAJKXSBWXTPA-UHFFFAOYSA-N COCCOC.COCCOC.COCCOC Chemical compound COCCOC.COCCOC.COCCOC MSPAJKXSBWXTPA-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 229940122866 Cannabinoid CB1 receptor inverse agonist Drugs 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 229920001268 Cholestyramine Polymers 0.000 description 1
- 229920002911 Colestipol Polymers 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 244000258136 Costus speciosus Species 0.000 description 1
- 235000000385 Costus speciosus Nutrition 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 206010070901 Diabetic dyslipidaemia Diseases 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 241001331845 Equus asinus x caballus Species 0.000 description 1
- 241001670226 Equus caballus x asinus Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Gemfibrozil Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 101710151321 Melanostatin Proteins 0.000 description 1
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 description 1
- 102100021316 Mineralocorticoid receptor Human genes 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 102400000064 Neuropeptide Y Human genes 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- WBWWGRHZICKQGZ-UHFFFAOYSA-N Taurocholic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(=O)NCCS(O)(=O)=O)C)C1(C)C(O)C2 WBWWGRHZICKQGZ-UHFFFAOYSA-N 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- JVVXZOOGOGPDRZ-SLFFLAALSA-N [(1R,4aS,10aR)-1,4a-dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine Chemical compound NC[C@]1(C)CCC[C@]2(C)C3=CC=C(C(C)C)C=C3CC[C@H]21 JVVXZOOGOGPDRZ-SLFFLAALSA-N 0.000 description 1
- SMEGJBVQLJJKKX-HOTMZDKISA-N [(2R,3S,4S,5R,6R)-5-acetyloxy-3,4,6-trihydroxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@@H]1[C@H]([C@@H]([C@H]([C@@H](O1)O)OC(=O)C)O)O SMEGJBVQLJJKKX-HOTMZDKISA-N 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000012042 active reagent Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- JIMXXGFJRDUSRO-UHFFFAOYSA-N adamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2CC1(C(=O)O)C3 JIMXXGFJRDUSRO-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000048 adrenergic agonist Substances 0.000 description 1
- 229940126157 adrenergic receptor agonist Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 description 1
- 125000005213 alkyl heteroaryl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000000137 annealing Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 235000021407 appetite control Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-L aspartate group Chemical class N[C@@H](CC(=O)[O-])C(=O)[O-] CKLJMWTZIZZHCS-REOHCLBHSA-L 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 229950010046 avasimibe Drugs 0.000 description 1
- 229940064856 azulfidine Drugs 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 229940076810 beta sitosterol Drugs 0.000 description 1
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 description 1
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 description 1
- 229960000516 bezafibrate Drugs 0.000 description 1
- IIBYAHWJQTYFKB-UHFFFAOYSA-N bezafibrate Chemical compound C1=CC(OC(C)(C)C(O)=O)=CC=C1CCNC(=O)C1=CC=C(Cl)C=C1 IIBYAHWJQTYFKB-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 108091022863 bile acid binding Proteins 0.000 description 1
- 102000030904 bile acid binding Human genes 0.000 description 1
- 229920000080 bile acid sequestrant Polymers 0.000 description 1
- 229940096699 bile acid sequestrants Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000012867 bioactive agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 229940054025 carbamate anxiolytics Drugs 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 230000021235 carbamoylation Effects 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical compound OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- GMRWGQCZJGVHKL-UHFFFAOYSA-N colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 description 1
- 229960002604 colestipol Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-O cyclohexylammonium Chemical group [NH3+]C1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-O 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 229960004597 dexfenfluramine Drugs 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-O dicyclohexylazanium Chemical class C1CCCCC1[NH2+]C1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-O 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- RMGVZKRVHHSUIM-UHFFFAOYSA-N dithionic acid Chemical compound OS(=O)(=O)S(O)(=O)=O RMGVZKRVHHSUIM-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000008846 dynamic interplay Effects 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000000871 endothelium corneal Anatomy 0.000 description 1
- 229950002375 englitazone Drugs 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 210000003560 epithelium corneal Anatomy 0.000 description 1
- LHWWETDBWVTKJO-UHFFFAOYSA-N et3n triethylamine Chemical compound CCN(CC)CC.CCN(CC)CC LHWWETDBWVTKJO-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- FPIQZBQZKBKLEI-UHFFFAOYSA-N ethyl 1-[[2-chloroethyl(nitroso)carbamoyl]amino]cyclohexane-1-carboxylate Chemical compound ClCCN(N=O)C(=O)NC1(C(=O)OCC)CCCCC1 FPIQZBQZKBKLEI-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 125000005469 ethylenyl group Chemical group 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000020375 flavoured syrup Nutrition 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000727 fraction Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950010772 glucose-1-phosphate Drugs 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- QFWPJPIVLCBXFJ-UHFFFAOYSA-N glymidine Chemical compound N1=CC(OCCOC)=CN=C1NS(=O)(=O)C1=CC=CC=C1 QFWPJPIVLCBXFJ-UHFFFAOYSA-N 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005553 heteroaryloxy group Chemical group 0.000 description 1
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 230000008801 hippocampal function Effects 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 206010021654 increased appetite Diseases 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000003455 independent Effects 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- OYIKARCXOQLFHF-UHFFFAOYSA-N isoxaflutole Chemical compound CS(=O)(=O)C1=CC(C(F)(F)F)=CC=C1C(=O)C1=C(C2CC2)ON=C1 OYIKARCXOQLFHF-UHFFFAOYSA-N 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000004701 malic acid derivatives Chemical class 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229950004994 meglitinide Drugs 0.000 description 1
- 230000006993 memory improvement Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical class C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- DTQCVJBGPGSUAT-UHFFFAOYSA-N n-cyclohexyl-n-methyl-1,3-thiazole-4-carboxamide Chemical compound C=1SC=NC=1C(=O)N(C)C1CCCCC1 DTQCVJBGPGSUAT-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- RFNRLZZYANHYOP-UHFFFAOYSA-N n-pentylpiperidine-1-carboxamide Chemical compound CCCCCNC(=O)N1CCCCC1 RFNRLZZYANHYOP-UHFFFAOYSA-N 0.000 description 1
- HSDXWKJHUJMEKM-UHFFFAOYSA-N n-propan-2-ylpiperidine-1-carboxamide Chemical compound CC(C)NC(=O)N1CCCCC1 HSDXWKJHUJMEKM-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- VYGZRRKABMHIHB-UHFFFAOYSA-N n-tert-butylpiperidine-1-carboxamide Chemical compound CC(C)(C)NC(=O)N1CCCCC1 VYGZRRKABMHIHB-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- PKWDZWYVIHVNKS-UHFFFAOYSA-N netoglitazone Chemical compound FC1=CC=CC=C1COC1=CC=C(C=C(CC2C(NC(=O)S2)=O)C=C2)C2=C1 PKWDZWYVIHVNKS-UHFFFAOYSA-N 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 230000024121 nodulation Effects 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- URPYMXQQVHTUDU-OFGSCBOVSA-N nucleopeptide y Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=C(O)C=C1 URPYMXQQVHTUDU-OFGSCBOVSA-N 0.000 description 1
- 125000005064 octadecenyl group Chemical group C(=CCCCCCCCCCCCCCCCC)* 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 229930029653 phosphoenolpyruvate Natural products 0.000 description 1
- DTBNBXWJWCWCIK-UHFFFAOYSA-N phosphoenolpyruvic acid Chemical compound OC(=O)C(=C)OP(O)(O)=O DTBNBXWJWCWCIK-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical class OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 210000000229 preadipocyte Anatomy 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000013930 proline Nutrition 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000006238 prop-1-en-1-yl group Chemical group [H]\C(*)=C(/[H])C([H])([H])[H] 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000002469 receptor inverse agonist Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- JZCPYUJPEARBJL-UHFFFAOYSA-N rimonabant Chemical compound CC=1C(C(=O)NN2CCCCC2)=NN(C=2C(=CC(Cl)=CC=2)Cl)C=1C1=CC=C(Cl)C=C1 JZCPYUJPEARBJL-UHFFFAOYSA-N 0.000 description 1
- 229960003015 rimonabant Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 230000036186 satiety Effects 0.000 description 1
- 235000019627 satiety Nutrition 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- 230000012488 skeletal system development Effects 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 210000005070 sphincter Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 108020003113 steroid hormone receptors Proteins 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003900 succinic acid esters Chemical class 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- DIORMHZUUKOISG-UHFFFAOYSA-N sulfoformic acid Chemical compound OC(=O)S(O)(=O)=O DIORMHZUUKOISG-UHFFFAOYSA-N 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- WBWWGRHZICKQGZ-GIHLXUJPSA-N taurocholic acid Chemical compound C([C@@H]1C[C@H]2O)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@H](O)C1 WBWWGRHZICKQGZ-GIHLXUJPSA-N 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- UOUFRTFWWBCVPV-UHFFFAOYSA-N tert-butyl 4-(2,4-dioxo-1H-thieno[3,2-d]pyrimidin-3-yl)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CC1)n1c(=O)[nH]c2ccsc2c1=O UOUFRTFWWBCVPV-UHFFFAOYSA-N 0.000 description 1
- SCGQNJHAAYUQOO-UHFFFAOYSA-N tert-butyl 4-carbamothioylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1 SCGQNJHAAYUQOO-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 210000001585 trabecular meshwork Anatomy 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/08—Antibacterial agents for leprosy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/46—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of glucocorticosteroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Neurology (AREA)
- Endocrinology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Communicable Diseases (AREA)
- Ophthalmology & Optometry (AREA)
- Heart & Thoracic Surgery (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Cardiology (AREA)
- Emergency Medicine (AREA)
- Rheumatology (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pulmonology (AREA)
- Dermatology (AREA)
- Child & Adolescent Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Vascular Medicine (AREA)
Abstract
The present invention relates to NIP thiazole derivatives of formula (I) as selective inhibitors of the enzyme 11--beta-hydroxysteroid dehydrogenase type 1(11-.beta.-HSD-1) and the use of such compounds for the treatment and prevention of metabolic syndrome, diabetes, insulin resistance, obesity, lipid disorders, glaucoma, osteoporosis, cognitive disorders, anxiety, depression, immune disorders, hypertension and other diseases and conditions.
Description
NIP Thiazole Derivatives as Inhibitors of 11-Beta-Hydroxysteroid Dehydrogenase-1 Description Technical field The present invention relates to Nip thiazoles derivatives as selective in-hibitors of enzyme 11-beta-hydroxysteroid dehydrogenase type 1 (11-p-HSD-1) and the use of such compounds for the treatment and/or prevention of metabolic syndrome, diabetes, insulin resistance, obesity, lipid disorders, glaucoma, osteoporosis, cognitive disorders, anxiety, depression, immune disorders, hypertension and other diseases and conditions.
Prior art Hydroxysteroid dehydrogenases (HSDs) regulate the occupancy and ac-tivation of steroid hormone receptors by converting steroid hormones into their inactive metabolites. For a recent review, see Nobel et al., Eur. J. Bio-chem. 2001, 268: 4113-4125.
There exist numerous classes of HSDs. The 11-beta-hydroxysteroid de-hydrogenases (11-p-HSDs) catalyze the interconversion of active glucocorti-coids (such as cortisol and corticosterone), and their inert forms (such as cortisone and 11-dehydrocorticosterone). The isoform 11-beta-hydroxysteroid dehydrogenase type 1 (11-13-HSD-1) is widely expressed in liver, adipose tissue, brain, lung and other glucocorticoid tissue, while the isoform 2 (11-13-HSD-2) expression is limited to tissues that express the min-eralocorticoid receptor, such as kidney, gut and placenta. Then the inhibition of 11p-HSD-2 is associated with serious side effects, such as hypertension.
Excess cortisol is associated with numerous disorders, including diabetes, obesity, dyslipidemia, insulin resistance and hypertension. The administration
Prior art Hydroxysteroid dehydrogenases (HSDs) regulate the occupancy and ac-tivation of steroid hormone receptors by converting steroid hormones into their inactive metabolites. For a recent review, see Nobel et al., Eur. J. Bio-chem. 2001, 268: 4113-4125.
There exist numerous classes of HSDs. The 11-beta-hydroxysteroid de-hydrogenases (11-p-HSDs) catalyze the interconversion of active glucocorti-coids (such as cortisol and corticosterone), and their inert forms (such as cortisone and 11-dehydrocorticosterone). The isoform 11-beta-hydroxysteroid dehydrogenase type 1 (11-13-HSD-1) is widely expressed in liver, adipose tissue, brain, lung and other glucocorticoid tissue, while the isoform 2 (11-13-HSD-2) expression is limited to tissues that express the min-eralocorticoid receptor, such as kidney, gut and placenta. Then the inhibition of 11p-HSD-2 is associated with serious side effects, such as hypertension.
Excess cortisol is associated with numerous disorders, including diabetes, obesity, dyslipidemia, insulin resistance and hypertension. The administration
- 2 -of 113-HSD-1 inhibitors decreases the level of cortisol and other 1113-hydroxysteroids in target tissues, thereby reducing the effects of excessive amounts of cortisol and other 113-hydroxysteroids. Thus, 11-13-HSD-1 is a potential target for therapy associated with numerous disorders that may be ameliorated by reduction of glucocorticoid action. Therefore, the inhibition of 11-p-HSD-1 can be used to prevent, treat or control diseases mediated by abnormally high levels of cortisol and other 110-hydroxysteroids, such as diabetes, obesity, hypertension or dyslipidemia. Inhibition of 11-p-HSD-1 ac-tivity in the brain such as to lower cortisol levels may also be useful to treat or reduce anxiety, depression, cognitive impairment or age-related cognitive dysfunction (Seckl, et al., Endocrinology, 2001, 142: 1371-1376).
Cortisol is an important and well recognized anti-inflammatory hormone, which also acts as an antagonist to the action of insulin in the liver, such that insulin sensitivity is reduced, resulting in increased gluconeogenesis and ele-vated levels of glucose in the liver. Patients who already have impaired glu-cose tolerance have a greater probability of developing type 2 diabetes in the presence of abnormally high levels of cortisol (Long et al., J. Exp. Med.
1936, 63: 465-490; Houssay, Endocrinology 1942, 30: 884-892). In addition, it has been well substantiated that 11-13-HSD-1 plays an important role in the regu-lation of local glucocorticoid effect and of glucose production in the liver (Jamieson et al., J. Endocrinol. 2000, 165: 685-692). In Walker, et al., J.
Clin.
Endocrinol. Metab. 1995, 80: 3155-3159, it was reported that the administra-tion of the non-specific 113-HSD-1 inhibitor carbenoxolone resulted in im-proved hepatic insulin sensitivity in humans.
Furthermore, the hypothesized mechanism of action of 11-p-HSD-1 in the treatment of diabetes has been supported by various experiments conducted in mice and rats. These studies showed that the mRNA levels and activities of two key enzymes in hepatic glucose production, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were reduced upon administration of 11-p-HSD-1 inhibitors. In addition, blood glucose lev-els and hepatic glucose production were shown to be reduced in 11-p-HSD-1
Cortisol is an important and well recognized anti-inflammatory hormone, which also acts as an antagonist to the action of insulin in the liver, such that insulin sensitivity is reduced, resulting in increased gluconeogenesis and ele-vated levels of glucose in the liver. Patients who already have impaired glu-cose tolerance have a greater probability of developing type 2 diabetes in the presence of abnormally high levels of cortisol (Long et al., J. Exp. Med.
1936, 63: 465-490; Houssay, Endocrinology 1942, 30: 884-892). In addition, it has been well substantiated that 11-13-HSD-1 plays an important role in the regu-lation of local glucocorticoid effect and of glucose production in the liver (Jamieson et al., J. Endocrinol. 2000, 165: 685-692). In Walker, et al., J.
Clin.
Endocrinol. Metab. 1995, 80: 3155-3159, it was reported that the administra-tion of the non-specific 113-HSD-1 inhibitor carbenoxolone resulted in im-proved hepatic insulin sensitivity in humans.
Furthermore, the hypothesized mechanism of action of 11-p-HSD-1 in the treatment of diabetes has been supported by various experiments conducted in mice and rats. These studies showed that the mRNA levels and activities of two key enzymes in hepatic glucose production, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) were reduced upon administration of 11-p-HSD-1 inhibitors. In addition, blood glucose lev-els and hepatic glucose production were shown to be reduced in 11-p-HSD-1
- 3 -knockout mice. Additional data gathered using this murine knockout model also confirm that inhibition of 11-p-HSD-1 will not cause hypoglycemia, since the basal levels of PEPCK and G6Pase are regulated independently of glu-cocorticoids (Kotelevtsev et al., Proc. Natl. Acad. Sci. USA 1997, 94: 14924-14929).
Therefore, the administration of a therapeutically effective amount of an 11-p-HSD-1 inhibitor is effective in treating, controlling and ameliorating the symptoms of diabetes, especially non-insulin dependent diabetes (NIDDM, type 2 diabetes mellitus) and administration of a therapeutically effective amount of an 11-p-HSD-1 inhibitor on a regular basis delays or prevents the onset of diabetes, particularly in humans.
The effect of elevated levels of cortisol is also observed in patients who have Cushing's Syndrome, which is a metabolic disease characterized by high levels of cortisol in the blood stream. Patients with Cushing's Syndrome often develop N1DDM.
Excessive levels of cortisol have been associated with obesity, perhaps due to increased hepatic gluconeogenesis. Abdominal obesity is closely as-sociated with glucose intolerance, diabetes, hyperinsulinemia, hypertriglyc-eridemia and other factors of Metabolic Syndrome, such as high blood pres-sure, elevated VLDL and reduced HDL (Montague et al., Diabetes, 2000, 49:
883-888). In obese subjects, 11-13-HSD-1 activity in adipose tissue is mark-edly increased and positively correlated with body mass. It has also been re-ported that inhibition of the 11-p-HSD-1 in pre-adipocytes (stromal cells) re-suited in a decreased rate of differentiation into adipocytes. This is predicted to result in diminished expansion (possibly reduction) of the omental fat de-pot, which may lead to reduced central obesity (Bujalska et al., Lancet 1997, 349: 1210-1213).
Thus, the administration of an effective amount of an 11-p-HSD-1 inhibitor is useful in the treatment or control of obesity. Long-term treatment with an 11-p-HSD-1 inhibitor is also useful in delaying or preventing the onset of
Therefore, the administration of a therapeutically effective amount of an 11-p-HSD-1 inhibitor is effective in treating, controlling and ameliorating the symptoms of diabetes, especially non-insulin dependent diabetes (NIDDM, type 2 diabetes mellitus) and administration of a therapeutically effective amount of an 11-p-HSD-1 inhibitor on a regular basis delays or prevents the onset of diabetes, particularly in humans.
The effect of elevated levels of cortisol is also observed in patients who have Cushing's Syndrome, which is a metabolic disease characterized by high levels of cortisol in the blood stream. Patients with Cushing's Syndrome often develop N1DDM.
Excessive levels of cortisol have been associated with obesity, perhaps due to increased hepatic gluconeogenesis. Abdominal obesity is closely as-sociated with glucose intolerance, diabetes, hyperinsulinemia, hypertriglyc-eridemia and other factors of Metabolic Syndrome, such as high blood pres-sure, elevated VLDL and reduced HDL (Montague et al., Diabetes, 2000, 49:
883-888). In obese subjects, 11-13-HSD-1 activity in adipose tissue is mark-edly increased and positively correlated with body mass. It has also been re-ported that inhibition of the 11-p-HSD-1 in pre-adipocytes (stromal cells) re-suited in a decreased rate of differentiation into adipocytes. This is predicted to result in diminished expansion (possibly reduction) of the omental fat de-pot, which may lead to reduced central obesity (Bujalska et al., Lancet 1997, 349: 1210-1213).
Thus, the administration of an effective amount of an 11-p-HSD-1 inhibitor is useful in the treatment or control of obesity. Long-term treatment with an 11-p-HSD-1 inhibitor is also useful in delaying or preventing the onset of
- 4 -obesity, especially if the patient uses an 11-13-HSD-1 inhibitor in combination with controlled diet end exercise.
By reducing insulin resistance and maintaining serum glucose at normal concentrations, compounds of the present invention also have utility in the treatment and prevention of conditions that accompany type 2 diabetes and insulin resistance, including the Metabolic Syndrome, obesity, reactive hypo-glycemia and diabetic dyslipidemia.
Inhibition of 11-p-HSD-1 in mature adipocytes is expected to attenuate secretion of the plasminogen activator inhibitor 1 (PAI-1), which is an inde-pendent cardiovascular risk factor, as reported in Halleux et al., J; Clin. En-docrinol. Metab. 1999, 84: 4097-4105. In addition, a correlation has been shown to exist between glucocorticoid activity and certain cardiovascular risk factors. This suggests that a reduction of the glucocorticoid effects would be beneficial in the treatment or prevention of certain cardiovascular diseases (Walker et al., Hypertension 1998, 31: 891-895; and Fraser et al., Hyperten-sion 1999, 33: 1364 1368).
Since hypertension and dyslipidemia contribute to the development of atherosclerosis and inhibition of 11-13-HSD-1 activity and a reduction in the amount of cortisol are beneficial in treating or controlling hypertension, ad-ministration of a therapeutically effective amount of an 11-p-HSD-1 inhibitor of the present invention may also be especially beneficial in treating, control-ling or delaying the onset of or preventing atherosclerosis.
11-f3-HSD-1 has also been implicated in the process of appetite control and therefore is believed to play an additional role in weight-related disor-ders. It is known that adrenalectomy attenuates the effect of fasting to in-crease both food intake and hypothalamic neuropeptide Y expression. This suggests that glucocorticoids play a role in promoting food intake and that in-hibition of 11-13-HSD-1 in the brain may increase satiety, thus resulting in a decreased food intake (Woods et al., Science 1998, 280: 1378-1383).
By reducing insulin resistance and maintaining serum glucose at normal concentrations, compounds of the present invention also have utility in the treatment and prevention of conditions that accompany type 2 diabetes and insulin resistance, including the Metabolic Syndrome, obesity, reactive hypo-glycemia and diabetic dyslipidemia.
Inhibition of 11-p-HSD-1 in mature adipocytes is expected to attenuate secretion of the plasminogen activator inhibitor 1 (PAI-1), which is an inde-pendent cardiovascular risk factor, as reported in Halleux et al., J; Clin. En-docrinol. Metab. 1999, 84: 4097-4105. In addition, a correlation has been shown to exist between glucocorticoid activity and certain cardiovascular risk factors. This suggests that a reduction of the glucocorticoid effects would be beneficial in the treatment or prevention of certain cardiovascular diseases (Walker et al., Hypertension 1998, 31: 891-895; and Fraser et al., Hyperten-sion 1999, 33: 1364 1368).
Since hypertension and dyslipidemia contribute to the development of atherosclerosis and inhibition of 11-13-HSD-1 activity and a reduction in the amount of cortisol are beneficial in treating or controlling hypertension, ad-ministration of a therapeutically effective amount of an 11-p-HSD-1 inhibitor of the present invention may also be especially beneficial in treating, control-ling or delaying the onset of or preventing atherosclerosis.
11-f3-HSD-1 has also been implicated in the process of appetite control and therefore is believed to play an additional role in weight-related disor-ders. It is known that adrenalectomy attenuates the effect of fasting to in-crease both food intake and hypothalamic neuropeptide Y expression. This suggests that glucocorticoids play a role in promoting food intake and that in-hibition of 11-13-HSD-1 in the brain may increase satiety, thus resulting in a decreased food intake (Woods et al., Science 1998, 280: 1378-1383).
- 5 -Another possible therapeutic effect associated with modulation of 11-13-HSD-1 is that which is related to various pancreatic aliments. It is reported that inhibition of 1113-HSD-1 in murine pancreatic 13-cells increases glucose stimulated insulin secretion (Davani et al., J. Biol. Chem. 2000, 275: 34841-34844). This follows from the preceding discovery that glucocorticoids were previously found to be responsible for reduced pancreatic insulin release in vivo (Billaudel et al., Horm. Metab. Res. 1979, 11: 555-560). Thus, it is sug-gested that inhibition of 11-13-HSD-1 would yield other beneficial effects in the treatment of diabetes other than the predicted effects on the liver and of fat reduction.
Excessive levels of cortisol in the brain may also result in neuronal loss or dysfunction through the potentiation of neurotoxins. Administration of an ef-fective amount of an 11-13-HSD-1 inhibitor results in the reduction, ameliora-tion, control or prevention of cognitive impairment associated with aging and of neuronal dysfunction. Cognitive impairment has been associated with ag-ing, and excess levels of cortisol in the brain (see J. R. Seckl and B. R.
Walker, Endocrinology, 2001, 142: 1371 1376, and references cited therein).
118-HSD-1 also regulates glucocorticoid activity in the brain and thus con-tributes to neurotoxicity (Rajan et al., Neuroscience 1996, 16: 65- 70; Seckl et al., Necroendocrinol. 2000, 18: 49-99). Stress and/or glucocorticoids are known to influence cognitive function (de Quervain et al., Nature 1998, 394:
787-790), and unpublished results indicate significant memory improvement in rats treated with a non-specific 118-HSD-1 inhibitor. These reports, in addi-tion to the known effects of glucocorticoids in the brain, suggest that inhibiting 118-HSD-1 in the brain may have a positive therapeutic effect against anxi-ety, depression and related conditions (Tronche et al., Nature Genetics 1999, 23: 99-103). 1113-HSD-1 reactivates 11-dehydrocorticosterone to corticoster-one in hippocampal cells and can potentiate kinase neurotoxicity, resulting in age-related learning impairments. Therefore, selective inhibitors of 1113-HSD-1 are believed to protect against hippocampal function decline with age (Yau et al., Proc Natl. Acad. Sci. USA 2001, 98: 4716-4721). Thus, it has been hy-
Excessive levels of cortisol in the brain may also result in neuronal loss or dysfunction through the potentiation of neurotoxins. Administration of an ef-fective amount of an 11-13-HSD-1 inhibitor results in the reduction, ameliora-tion, control or prevention of cognitive impairment associated with aging and of neuronal dysfunction. Cognitive impairment has been associated with ag-ing, and excess levels of cortisol in the brain (see J. R. Seckl and B. R.
Walker, Endocrinology, 2001, 142: 1371 1376, and references cited therein).
118-HSD-1 also regulates glucocorticoid activity in the brain and thus con-tributes to neurotoxicity (Rajan et al., Neuroscience 1996, 16: 65- 70; Seckl et al., Necroendocrinol. 2000, 18: 49-99). Stress and/or glucocorticoids are known to influence cognitive function (de Quervain et al., Nature 1998, 394:
787-790), and unpublished results indicate significant memory improvement in rats treated with a non-specific 118-HSD-1 inhibitor. These reports, in addi-tion to the known effects of glucocorticoids in the brain, suggest that inhibiting 118-HSD-1 in the brain may have a positive therapeutic effect against anxi-ety, depression and related conditions (Tronche et al., Nature Genetics 1999, 23: 99-103). 1113-HSD-1 reactivates 11-dehydrocorticosterone to corticoster-one in hippocampal cells and can potentiate kinase neurotoxicity, resulting in age-related learning impairments. Therefore, selective inhibitors of 1113-HSD-1 are believed to protect against hippocampal function decline with age (Yau et al., Proc Natl. Acad. Sci. USA 2001, 98: 4716-4721). Thus, it has been hy-
- 6 -pothesized that inhibition of 11p-HSD-1 in the human brain would protect against deleterious glucocorticoid-mediated effects on neuronal function, such as cognitive impairment, depression, and increased appetite.
Furthermore, 113-HSD-1 is believed to play a role in immunomodulation based on the general perception that glucocorticoids suppress the immune system. There is known to be a dynamic interaction between the immune system and the HPA (hypothalamic-pituitary-adrenal) axis (Rook, Baillier's Clin. Endocrinol. Metab. 2000, 13: 576-581), and glucocorticoids help bal-ance between cell-mediated responses and humoral responses.
Increased glucocorticoid activity, which may be induced by stress, is as-sociated with a humoral response and as such, the inhibition of 11p-HSD-1 may result in shifting the response towards a cell-based reaction. In certain disease states, such as tuberculosis, leprosy and psoriasis, and even under conditions of excessive stress, high glucocorticoid activity shifts the immune response to a humoral response, when in fact a cell based response may be more beneficial to the patient. Inhibition of 110-HSD-1 activity and the atten-dant reduction in glucocorticoid levels on the other hand shifts the immune response toward a cell based response (D. Mason, Immunology Today, 1991, 12: 57-60, and G.A.Vt. Rook, Baillier's Clin. Endocrinol. Metab., 1999, 13: 576-581). It follows then, that an alternative utility of 110-HSD-1 inhibition would be to bolster a temporal immune response in association with immuni-zation to ensure that a cell based response would be obtained.
Recent reports suggest that the levels of glucocorticoid target receptors and of HSDs are connected with the susceptibility to glaucoma (J. Stokes et al., Invest. Ophthalmol. 2000, 41: 1629-1638). Further, a connection between inhibition of 113-HSD-1 and a lowering of the intraocular pressure was re-cently reported (Walker et al., poster P3-698 at the Endocrine society meet-ing June 12-15, 1999, San Diego). It was shown that administration of the nonspecific 113-HSD-1 inhibitor carbenoxolone resulted in the reduction of the intraocular pressure by 20% in normal patients. In the eye, 110-HSD-1 is expressed exclusively in the basal cells of the corneal epithelium, the non-
Furthermore, 113-HSD-1 is believed to play a role in immunomodulation based on the general perception that glucocorticoids suppress the immune system. There is known to be a dynamic interaction between the immune system and the HPA (hypothalamic-pituitary-adrenal) axis (Rook, Baillier's Clin. Endocrinol. Metab. 2000, 13: 576-581), and glucocorticoids help bal-ance between cell-mediated responses and humoral responses.
Increased glucocorticoid activity, which may be induced by stress, is as-sociated with a humoral response and as such, the inhibition of 11p-HSD-1 may result in shifting the response towards a cell-based reaction. In certain disease states, such as tuberculosis, leprosy and psoriasis, and even under conditions of excessive stress, high glucocorticoid activity shifts the immune response to a humoral response, when in fact a cell based response may be more beneficial to the patient. Inhibition of 110-HSD-1 activity and the atten-dant reduction in glucocorticoid levels on the other hand shifts the immune response toward a cell based response (D. Mason, Immunology Today, 1991, 12: 57-60, and G.A.Vt. Rook, Baillier's Clin. Endocrinol. Metab., 1999, 13: 576-581). It follows then, that an alternative utility of 110-HSD-1 inhibition would be to bolster a temporal immune response in association with immuni-zation to ensure that a cell based response would be obtained.
Recent reports suggest that the levels of glucocorticoid target receptors and of HSDs are connected with the susceptibility to glaucoma (J. Stokes et al., Invest. Ophthalmol. 2000, 41: 1629-1638). Further, a connection between inhibition of 113-HSD-1 and a lowering of the intraocular pressure was re-cently reported (Walker et al., poster P3-698 at the Endocrine society meet-ing June 12-15, 1999, San Diego). It was shown that administration of the nonspecific 113-HSD-1 inhibitor carbenoxolone resulted in the reduction of the intraocular pressure by 20% in normal patients. In the eye, 110-HSD-1 is expressed exclusively in the basal cells of the corneal epithelium, the non-
- 7 -pigmented epithelium of the cornea (the site of aqueous production), ciliary muscle, and the sphincter and dilator muscles of the iris. In contrast, the dis-tant isoenzyme 11-hydroxysteroid dehydrogenase type 2 ("11-13-HSD-2") is highly expressed in the non-pigmented ciliary epithelium and corneal endo-thelium. No HSDs have been found at the trabecular meshwork, which is the site of drainage. Therefore, 11-0-HSD-1 is suggested to have a role in aque-ous production and inhibition of 11-13-HSD-1 activity is useful in reducing in-traocular pressure in the treatment of glaucoma.
Glucocorticoids also play an essential role in skeletal development and function but are detrimental to such development and function when present in excess. Glucocorticoid-induced bone loss is partially derived from sup-pression of osteoblast proliferation and collagen synthesis, as reported in C.
H. Kim et al., J. Endocrinol. 1999, 162: 371 379. It has been reported that the detrimental effects of glucocorticoids on bone nodule formation can be less-ened by administration of carbenoxolone, which is a non-specific 11-p-HSD-1 inhibitor (C. G. Bellows et al., Bone 1998, 23: 119-125). Additional reports suggest that 11-p-HSD-1 maybe responsible for providing increased levels of active glucocorticoid in osteoclasts, and thus in augmenting bone resorption (M. S. Cooper et at, Bone 2000, 27: 375-381). This data suggests that inhibi-tion of 11-13-HSD-1 may have beneficial effects against osteoporosis via one or more mechanisms which may act in parallel.
11-p-HSD-1 inhibitors are known e.g. from the WO 04/10629, WO 03/065983, WO 04/089896, WO 04/089380, WO 04/065351, WO 04/033427 or WO 04/041264. For a recent review see M. Wamil and J.R.Seckl (Drug Discovery Today; June 2007, page 504-520) and C.D.Boyle, T.J.Kowalski and L.Zhang (Annual reports in medicinal chemistry; 2006, 41, 127-140). However, Nip thiazoles are not disclosed as active 11-p-HSD-1 in-hibitors.
Thiazoles derivatives are disclosed for example in WO 2007/11805, WO 2007/123269, WO 2007/104557, WO 2007/104558, EP 1 832 586, WO 2007/014290, WO 2007/016979, WO 2006/032322, WO 2005/116653,
Glucocorticoids also play an essential role in skeletal development and function but are detrimental to such development and function when present in excess. Glucocorticoid-induced bone loss is partially derived from sup-pression of osteoblast proliferation and collagen synthesis, as reported in C.
H. Kim et al., J. Endocrinol. 1999, 162: 371 379. It has been reported that the detrimental effects of glucocorticoids on bone nodule formation can be less-ened by administration of carbenoxolone, which is a non-specific 11-p-HSD-1 inhibitor (C. G. Bellows et al., Bone 1998, 23: 119-125). Additional reports suggest that 11-p-HSD-1 maybe responsible for providing increased levels of active glucocorticoid in osteoclasts, and thus in augmenting bone resorption (M. S. Cooper et at, Bone 2000, 27: 375-381). This data suggests that inhibi-tion of 11-13-HSD-1 may have beneficial effects against osteoporosis via one or more mechanisms which may act in parallel.
11-p-HSD-1 inhibitors are known e.g. from the WO 04/10629, WO 03/065983, WO 04/089896, WO 04/089380, WO 04/065351, WO 04/033427 or WO 04/041264. For a recent review see M. Wamil and J.R.Seckl (Drug Discovery Today; June 2007, page 504-520) and C.D.Boyle, T.J.Kowalski and L.Zhang (Annual reports in medicinal chemistry; 2006, 41, 127-140). However, Nip thiazoles are not disclosed as active 11-p-HSD-1 in-hibitors.
Thiazoles derivatives are disclosed for example in WO 2007/11805, WO 2007/123269, WO 2007/104557, WO 2007/104558, EP 1 832 586, WO 2007/014290, WO 2007/016979, WO 2006/032322, WO 2005/116653,
- 8 -WO 2005/074934, WO 2004/058751, WO 2004/058750, WO 2004/041815, WO 2001/74788, WO 97/15567, WO 2005/113522, US 2005/0250784, US 2005/0234033, WO 2005/049018, WO 02/088093, WO 98/46599, WO 98/28282, WO 96/25414, US 2006/247253, US 2006/069102, FR 2865733, FR 2856685, Leban J et al., (Bioorg Med Chem Let 2007, 17:
5858-5862) and Xing L et al., (J Comp Molec Design 2004, 18: 333-344).
The disclosure of these publications, however, does not encompass the Nip thiazoles derivatives of the present invention nor the use of the disclosed compounds as 11-p-HSD-1 inhibitors.
The citation of any reference in this application is not an admission that the reference is prior art to this application.
Description of the invention The present invention has the object to provide novel thiazole derivatives that act as 11-p-HSD-1 inhibitors.
The object of the present invention has surprisingly been solved in one aspect by providing the use of a thiazole derivative according to formula (I) R1, N---kc N / _____________________ \
42 I N¨X
S ______________________________ / \ pp 1 ..... (I) wherein:
R1, R2 are independently from each other alkyl, cycloalkyl or heterocy-clyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by at least one substituent selected from alkyl, cycloalkyl or hydroxyl, or R1, R2 and the nitrogen to which they are attached form a saturated mono- or bi-cyclic ring containing 3-20, preferably 6-10 atoms, optionally containing at
5858-5862) and Xing L et al., (J Comp Molec Design 2004, 18: 333-344).
The disclosure of these publications, however, does not encompass the Nip thiazoles derivatives of the present invention nor the use of the disclosed compounds as 11-p-HSD-1 inhibitors.
The citation of any reference in this application is not an admission that the reference is prior art to this application.
Description of the invention The present invention has the object to provide novel thiazole derivatives that act as 11-p-HSD-1 inhibitors.
The object of the present invention has surprisingly been solved in one aspect by providing the use of a thiazole derivative according to formula (I) R1, N---kc N / _____________________ \
42 I N¨X
S ______________________________ / \ pp 1 ..... (I) wherein:
R1, R2 are independently from each other alkyl, cycloalkyl or heterocy-clyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by at least one substituent selected from alkyl, cycloalkyl or hydroxyl, or R1, R2 and the nitrogen to which they are attached form a saturated mono- or bi-cyclic ring containing 3-20, preferably 6-10 atoms, optionally containing at
- 9 -least one further heteroatom selected from N, S or 0 and optionally being substituted by at least one substituent selected from halogen, alkyl, hydroxyl, =0 (carbonyl oxygen), aryl or heteroaryl;
R3 is alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl or het-eroaryl-alkyl, wherein alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, het-eroaryl or heteroaryl-alkyl is optionally substituted by at least one substituent selected from halogen, hydroxyl, C(0)0H, CN, C(0)-NH2, carbamoyl, acetamide, alkyl, aryl, phenyl, methoxy-phenyl, fluorophenyl, phenoxy, ary-loxy, alkyloxy, Craralkyloxy, methoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyloxycarbonyl, Craralkyloxycarbonyl, alkylcarbonyl, C1-C4-alkylcarbonyl, R4R5NC1-C4-alkyloxy, or C1-C4-alkyl-S(0), wherein n is 0,1 or 2;
R4, R5 are independently from each other alkyl or cycloalkyl;
X is a direct bond, C(0), C(0)0, S(0)2 or C(0)NH;
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios, as 11-13-HSD-1 inhibitor.
In a preferred embodiment, the use of thiazole derivatives according to for-mula (I) as 11-p-HSD-1 inhibitor is provided, wherein R1, R2 are independently from each other alkyl or cycloalkyl optionally substituted by at least one substituent selected from alkyl, cycloalkyl or hy-droxyl, and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-p-HSD-1 inhibitor is provided, wherein
R3 is alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl or het-eroaryl-alkyl, wherein alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, het-eroaryl or heteroaryl-alkyl is optionally substituted by at least one substituent selected from halogen, hydroxyl, C(0)0H, CN, C(0)-NH2, carbamoyl, acetamide, alkyl, aryl, phenyl, methoxy-phenyl, fluorophenyl, phenoxy, ary-loxy, alkyloxy, Craralkyloxy, methoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyloxycarbonyl, Craralkyloxycarbonyl, alkylcarbonyl, C1-C4-alkylcarbonyl, R4R5NC1-C4-alkyloxy, or C1-C4-alkyl-S(0), wherein n is 0,1 or 2;
R4, R5 are independently from each other alkyl or cycloalkyl;
X is a direct bond, C(0), C(0)0, S(0)2 or C(0)NH;
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios, as 11-13-HSD-1 inhibitor.
In a preferred embodiment, the use of thiazole derivatives according to for-mula (I) as 11-p-HSD-1 inhibitor is provided, wherein R1, R2 are independently from each other alkyl or cycloalkyl optionally substituted by at least one substituent selected from alkyl, cycloalkyl or hy-droxyl, and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-p-HSD-1 inhibitor is provided, wherein
- 10 -R1, R2 are independently from each other methyl, cyclopropyl or cyclo-hexyl, optionally substituted by at least one substituent selected from alkyl, cycloalkyl or hydroxyl, and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-13-HSD-1 inhibitor is provided, wherein R1, R2 and the nitrogen to which they are attached form a saturated mono- or bicyclic ring containing 6-10 atoms, optionally being substituted by at least one substituent selected from halogen, alkyl, hydroxyl, =0 (carbonyl oxygen), aryl or heteroaryl.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-13-HSD-1 inhibitor is provided, wherein R1, R2 and the nitrogen to which they are attached form piperidine or oc-tahydroquinoline, optionally being substituted by at least one substituent se-lected from halogen, alkyl, hydroxyl, =0 (carbonyl oxygen), aryl or heteroaryl.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 1143-HSD-1 inhibitor is provided, wherein X is a direct bond;
R3 is alkyl, cycloalkyl-alkyl or heterocyclyl-alkyl, optionally substituted by at least one substituent selected from halogen, hydroxyl, C(0)0H, CN, C(0)-
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-13-HSD-1 inhibitor is provided, wherein R1, R2 and the nitrogen to which they are attached form a saturated mono- or bicyclic ring containing 6-10 atoms, optionally being substituted by at least one substituent selected from halogen, alkyl, hydroxyl, =0 (carbonyl oxygen), aryl or heteroaryl.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-13-HSD-1 inhibitor is provided, wherein R1, R2 and the nitrogen to which they are attached form piperidine or oc-tahydroquinoline, optionally being substituted by at least one substituent se-lected from halogen, alkyl, hydroxyl, =0 (carbonyl oxygen), aryl or heteroaryl.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 1143-HSD-1 inhibitor is provided, wherein X is a direct bond;
R3 is alkyl, cycloalkyl-alkyl or heterocyclyl-alkyl, optionally substituted by at least one substituent selected from halogen, hydroxyl, C(0)0H, CN, C(0)-
-11 -NH2, carbamoyl, acetamide, alkyl, aryl, phenyl, methoxy-phenyl, fluoro-phenyl, phenoxy, aryloxy, alkyloxy, C1-C4-alkyloxy, methoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyloxycarbonyl, C1-C4-alkyloxycarbonyl, alkylcarbonyl, C1-C4-alkylcarbonyl, R4R5NC1-C4-alkyloxy, or Ci-C4-alkyl-S(0)n, wherein n is 0, 1 or 2.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-13-HSD-1 inhibitor is provided, wherein X is a direct bond;
R3 is cyclohexyl-methyl, cyclohexyl-ethyl, tetrahydropyryl-methyl, cyano-methyl, pentyl, isobutyl, butyl, methyl-butyl or aminocarbonyl-methyl.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-13-HSD-1 inhibitor is provided, wherein X is C(0) or C(0)0;
R3 is alkyl, cycloalkyl, aryl or heteroaryl, optionally substituted by at least one substituent selected from halogen, hydroxyl, C(0)0H, CN, C(0)-NH2, carbamoyl, acetamide, alkyl, aryl, phenyl, methoxy-phenyl, fluorophenyl, phenoxy, aryloxy, alkyloxy, C1-C4-alkyloxy, methoxy, trifluoromethyl, trifluo-romethoxy, trifluoromethylthio, alkyloxycarbonyl, C1-C4-alkyloxycarbonyl, al-kylcarbonyl, C1-C4-alkylcarbonyl, R4R5NC1-C4-alkyloxy, or C1-C4-alkyl-S(0)n, wherein n is 0, 1 or 2.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-13-HSD-1 inhibitor is provided, wherein X is a direct bond;
R3 is cyclohexyl-methyl, cyclohexyl-ethyl, tetrahydropyryl-methyl, cyano-methyl, pentyl, isobutyl, butyl, methyl-butyl or aminocarbonyl-methyl.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-13-HSD-1 inhibitor is provided, wherein X is C(0) or C(0)0;
R3 is alkyl, cycloalkyl, aryl or heteroaryl, optionally substituted by at least one substituent selected from halogen, hydroxyl, C(0)0H, CN, C(0)-NH2, carbamoyl, acetamide, alkyl, aryl, phenyl, methoxy-phenyl, fluorophenyl, phenoxy, aryloxy, alkyloxy, C1-C4-alkyloxy, methoxy, trifluoromethyl, trifluo-romethoxy, trifluoromethylthio, alkyloxycarbonyl, C1-C4-alkyloxycarbonyl, al-kylcarbonyl, C1-C4-alkylcarbonyl, R4R5NC1-C4-alkyloxy, or C1-C4-alkyl-S(0)n, wherein n is 0, 1 or 2.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
- 12 -In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-p-HSD-1 inhibitor is provided, wherein X is C(0) or C(0)0;
R3 is methyl, ethyl, propyl, dimethyl-propyl, butyl, pentyl, tert. butyl, cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or pyridinyl, optionally substituted by at least one substituent selected from halogen, hydroxyl, C(0)0H, CN, C(0)-NH2, carbamoyl, acetamide, alkyl, aryl, phenyl, methoxy-phenyl, fluorophenyl, phenoxy, aryloxy, alkyloxy, C1-C4-alkyloxy, methoxy, tri-fluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyloxycarbonyl, C1-C4-alkyloxycarbonyl, alkylcarbonyl, C1-C4-alkylcarbonyl, R4R5NC1-C4-alkyloxy, or C1-C4-alkyl-S(0)n, wherein n is 0, 1 or 2.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-p-HSD-1 inhibitor is provided, wherein X is C(0)NH;
R3 is alkyl or cycloalkyl, optionally substituted by at least one substituent selected from halogen, hydroxyl, C(0)0H, CN, C(0)-NH2, carbamoyl, acetamide, alkyl, aryl, phenyl, methoxy-phenyl, fluorophenyl, phenoxy, ary-loxy, alkyloxy, C1-C4-alkyloxy, methoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyloxycarbonyl, C1-C4-alkyloxycarbonyl, alkylcarbonyl, C1-C4-alkylcarbonyl, R4R5NC1-C4-alkyloxy, or C,-C4-alkyl-S(0), wherein n is 0,1 or 2.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
R3 is methyl, ethyl, propyl, dimethyl-propyl, butyl, pentyl, tert. butyl, cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl or pyridinyl, optionally substituted by at least one substituent selected from halogen, hydroxyl, C(0)0H, CN, C(0)-NH2, carbamoyl, acetamide, alkyl, aryl, phenyl, methoxy-phenyl, fluorophenyl, phenoxy, aryloxy, alkyloxy, C1-C4-alkyloxy, methoxy, tri-fluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyloxycarbonyl, C1-C4-alkyloxycarbonyl, alkylcarbonyl, C1-C4-alkylcarbonyl, R4R5NC1-C4-alkyloxy, or C1-C4-alkyl-S(0)n, wherein n is 0, 1 or 2.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-p-HSD-1 inhibitor is provided, wherein X is C(0)NH;
R3 is alkyl or cycloalkyl, optionally substituted by at least one substituent selected from halogen, hydroxyl, C(0)0H, CN, C(0)-NH2, carbamoyl, acetamide, alkyl, aryl, phenyl, methoxy-phenyl, fluorophenyl, phenoxy, ary-loxy, alkyloxy, C1-C4-alkyloxy, methoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyloxycarbonyl, C1-C4-alkyloxycarbonyl, alkylcarbonyl, C1-C4-alkylcarbonyl, R4R5NC1-C4-alkyloxy, or C,-C4-alkyl-S(0), wherein n is 0,1 or 2.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
- 13 -In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-0-HSD-1 inhibitor is provided, wherein X is C(0)NH;
R3 is ethyl, propyl, isopropyl, butyl, pentyl or cyclopentyl.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-13-HSD-1 inhibitor is provided, wherein X is S(0)2;
R3 is alkyl, aryl, heteroaryl, aryl-alkyl or heteroaryl-alkyl, optionally substi-tuted by at least one substituent selected from halogen, hydroxyl, C(0)0H, CN, C(0)-NH2, carbamoyl, acetamide, alkyl, aryl, phenyl, methoxy-phenyl, fluorophenyl, phenoxy, aryloxy, alkyloxy, C1-C4-alkyloxy, methoxy, trifluoro-methyl, trifluoromethoxy, trifluoromethylthio, alkyloxycarbonyl, C1-C4-alkyloxycarbonyl, alkylcarbonyl, C1-C4-alkylcarbonyl, R4R5NC1-C4-alkyloxy, or C1-C4-alkyl-S(0), wherein n is 0, 1 or 2.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-p-HSD-1 inhibitor is provided, wherein X is S(0)2, R3 is methyl, ethyl, propyl, butyl, phenyl-methyl, pyridinyl-ethyl or thio-phenyl, optionally substituted by at least one substituent selected from halo-gen, hydroxyl, C(0)0H, CN, C(0)-NH2, carbamoyl, acetamide, alkyl, aryl, phenyl, methoxy-phenyl, fluorophenyl, phenoxy, aryloxy, alkyloxy, C1-C4-alkyloxy, methoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alky-
R3 is ethyl, propyl, isopropyl, butyl, pentyl or cyclopentyl.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-13-HSD-1 inhibitor is provided, wherein X is S(0)2;
R3 is alkyl, aryl, heteroaryl, aryl-alkyl or heteroaryl-alkyl, optionally substi-tuted by at least one substituent selected from halogen, hydroxyl, C(0)0H, CN, C(0)-NH2, carbamoyl, acetamide, alkyl, aryl, phenyl, methoxy-phenyl, fluorophenyl, phenoxy, aryloxy, alkyloxy, C1-C4-alkyloxy, methoxy, trifluoro-methyl, trifluoromethoxy, trifluoromethylthio, alkyloxycarbonyl, C1-C4-alkyloxycarbonyl, alkylcarbonyl, C1-C4-alkylcarbonyl, R4R5NC1-C4-alkyloxy, or C1-C4-alkyl-S(0), wherein n is 0, 1 or 2.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, the use of thiazole derivatives according to formula (I) as 11-p-HSD-1 inhibitor is provided, wherein X is S(0)2, R3 is methyl, ethyl, propyl, butyl, phenyl-methyl, pyridinyl-ethyl or thio-phenyl, optionally substituted by at least one substituent selected from halo-gen, hydroxyl, C(0)0H, CN, C(0)-NH2, carbamoyl, acetamide, alkyl, aryl, phenyl, methoxy-phenyl, fluorophenyl, phenoxy, aryloxy, alkyloxy, C1-C4-alkyloxy, methoxy, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alky-
- 14 -loxycarbonyl, C1-aralkyloxycarbonyl, alkylcarbonyl, C1-C4-alkylcarbonyl, R4R5NC1-C4-alkyloxy, or C1-C4-alkyl-S(0), wherein n is 0, 1 or 2.
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, thiazole derivatives according to formula (I) and above preferred embodiments and their use as 11-I3-HSD-1 inhibitors are provided that are selected from the group consisting of:
a) 3,3-Dimethy1-1-{444-(octahydro-quinoline-1-carbonyl)-thiazol-2-yll-piperidin-1-y1}-butan-1-one b) (Octahydro-quinolin-1-y1)-{241-(pyridine-3-carbony1)-piperidin-4-y1)-thiazol-4-y1}-methanone c) 2-(1-Cyclohexanecarbonyl-piperidin-4-y1)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide d) 2-(1-Cyclopentanecarbonyl-piperidin-4-y1)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide e) 2-(1-Cyclobutanecarbonyl-piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide f) 2-(1-Cyclopropanecarbonyl-piperidin-4-y1)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide g) 241-(3-Cyclopentyl-propiony1)-piperidin-4-ylPhiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide h) 241-(2-Ethyl-butyry1)-piperidin-4-ylPhiazole-4-carboxylic acid cyclo-hexyl-cyclopropyl-amide i) 241-(3,3-Dimethyl-butyryl)-piperidin-4-ylphiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide j) 211-(3-Methyl-butyryl)-piperidin-4-ylPhiazole-4-carboxylic acid cyclo-hexyl-cyclopropyl-amide
and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
In a preferred embodiment, thiazole derivatives according to formula (I) and above preferred embodiments and their use as 11-I3-HSD-1 inhibitors are provided that are selected from the group consisting of:
a) 3,3-Dimethy1-1-{444-(octahydro-quinoline-1-carbonyl)-thiazol-2-yll-piperidin-1-y1}-butan-1-one b) (Octahydro-quinolin-1-y1)-{241-(pyridine-3-carbony1)-piperidin-4-y1)-thiazol-4-y1}-methanone c) 2-(1-Cyclohexanecarbonyl-piperidin-4-y1)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide d) 2-(1-Cyclopentanecarbonyl-piperidin-4-y1)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide e) 2-(1-Cyclobutanecarbonyl-piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide f) 2-(1-Cyclopropanecarbonyl-piperidin-4-y1)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide g) 241-(3-Cyclopentyl-propiony1)-piperidin-4-ylPhiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide h) 241-(2-Ethyl-butyry1)-piperidin-4-ylPhiazole-4-carboxylic acid cyclo-hexyl-cyclopropyl-amide i) 241-(3,3-Dimethyl-butyryl)-piperidin-4-ylphiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide j) 211-(3-Methyl-butyryl)-piperidin-4-ylPhiazole-4-carboxylic acid cyclo-hexyl-cyclopropyl-amide
- 15 -k) 2-(1-lsobutyryl-piperidin-4-y1)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide I) 2-(1-Pentanoyl-piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide m) 2-(1-Propionyl-piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide n) 2-(1-Acetyl-piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 0) 2-[1-(Pyridine-3-carbony1)-piperidin-4-y1]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide p) 241-(4-Trifluoromethoxy-benzoy1)-piperidin-4-y11-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide q) [2-(1-Cyclohexanecarbonyl-piperidin-4-y1)-thiazol-4-y1]-(octahydro-quinolin-1-y1)-methanone r) [2-(1-Cyclopentanecarbonyl-piperidin-4-y1)-thiazol-4-y1]-(octahydro-quinolin-1-y1)-methanone s) [2-(1-Cyclobutanecarbonyl-piperidin-4-y1)-thiazol-4-y1]-(octahydro-quinolin-1-y1)-methanone t) [2-(1-Cyclopropanecarbonyl-piperidin-4-y1)-thiazol-4-y1]-(octahydro-quinolin-1-y1)-methanone u) 3-Cyclopenty1-1-{4-[4-(octahydro-quinoline-1-carbony1)-thiazol-2-y1]-piperidin-1 -01-propan-1 -one v) 2-Ethy1-1-{444-(octahydro-quinoline-1-carbony1)-thiazol-2-y1]-piperidin-1-y1}-butan-1-one w) 3-Methy1-1-{444-(octahydro-quinoline-1-carbony1)-thiazol-2-y11-piperidin-1-y1}-butan-1-one x) 2-Methy1-1-{444-(octahydro-quinoline-1-carbonyl)-thiazol-2-y1J-piperidin-1-y1}-propan-1-one
- 16 -y) 1-{444-(Octahydro-quinoline-1-carbony1)-thiazol-2-ylypiperidin-1-y1}-pentan-1-one z) 1-{444-(Octahydro-quinoline-1-carbony1)-thiazol-2-yll-piperidin-1-y1}-propan-1-one aa) 1-1444-(Octahydro-quinoline-1-carbony1)-thiazol-2-y1]-piperidin-1-yll-ethanone bb) (Octahydro-quinolin-1-yl)-{211-(4-trifluoromethoxy-benzoy1)-piperidin-4-y11-thiazo{-4-y1}-methanone cc) {241-(4-Fluoro-benzoy1)-piperidin-4-yli-thiazol-4-y1)-(octahydro-quinolin-1-y1)-methanone dd) {211-(4-Fluoro-benzoy1)-piperidin-4-y1J-thiazol-4-y1)-(4-hydroxy-octahydro-quinolin-1-y1)-methanone ee) 1-1444-(4-Hydroxy-octahydro-quinoline-1-carbonyl)-thiazol-2-yli-piperidin-1-y1}-2-(4-methoxy-pheny1)-ethanone if) 444-(4-Hydroxy-octahydro-quinoline-1-carbony1)-thiazol-2-A-piperidine-1-carboxylic acid tert-butyl ester gg) 241-(2-Phenyl-butyry1)-piperidin-4-yll-thiazole-4-carboxylic acid cyclo-hexyl-cyclopropyl-amide hh) 2-{112-(4-Methoxy-pheny1)-acetyll-piperidin-4-y1}-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide ii) 241-(2-Phenoxy-acety1)-piperidin-4-A-thiazole-4-carboxylic acid cyclo-hexyl-cyclopropyl-amide jj) 444-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-yll-piperidine-1-carboxylic acid tert-butyl ester kk) 1-{444-(Octahydro-quinoline-l-carbony1)-thiazol-2-y1J-piperidin-1-y1}-2-phenyl-butan-l-one II) 2-(4-Methoxy-pheny1)-1-{444-(octahydro-quinoline-1-carbony1)-thiazol-2-y1J-piperidin-1-y1}-ethanone
- 17 -mm)14444-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yli-piperidin-1-y1}-2-phenoxy-ethanone nn) 444-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yli-piperidine-1-carboxylic acid tert-butyl ester oo) 2-Phenyl-1-{444-(piperidine-1-carbonyl)-thiazol-2-y1]-piperidin-1-y1}-butan-1-one pp) 2-(4-Methoxy-phenyl)-1-{444-(piperidine-1-carbonyl)-thiazol-2-y11-piperidin-1-ylyethanone qq) 2-Phenoxy-1-{444-(piperidine-1-carbonyl)-thiazol-2-y1Fpiperidin-1-y1}-ethanone rr) 4[4-(Piperidine-1-carbonyl)-thiazol-2-y1]-piperidine-1-carboxylic acid tert-butyl ester ss) 241-(2-Phenyl-butyry1)-piperidin-4-y1Fthiazole-4-carboxylic acid cyclo-hexyl-methyl-amide tt) 2-{142-(4-Methoxy-phenyl)-acetyl]-piperidin-4-y1}-thiazole-4-carboxylic acid cyclohexyl-methyl-amide uu) 211-(2-Phenoxy-acetyl)-piperidin-4-yli-thiazole-4-carboxylic acid cyclo-hexyl-methyl-amide vv) 444-(Octahydro-quinoline-l-carbonylythiazol-2-yll-piperidine-1-carboxylic acid sec-butylamide ww) 444-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yli-piperidine-1-carboxylic acid tert-butylamide xx) 444-(Octahydro-quinoline-1-carbonyl)-thiazol-2-y11-piperidine-1-carboxylic acid propylamide yy) 444-(Octahydro-quinoline-1-carbonyl)-thiazol-2-y1]-piperidine-1-carboxylic acid ethylamide zz) 444-(Octahydro-quinoline-1-carbonyl)-thiazol-2-y1]-piperidine-1-carboxylic acid cyclopentylamide
- 18 -aaa) 4[4-(Octahyd ro-q uinol ine-1-carbonyl)-thiazol-2-y11-piperid ine-1-carboxylic acid isopropylamide bbb) 4[4-(Octahydro-q uinoline-1-carbonyl)-thiazol-2-y1]-piperidine-1-carboxylic acid pentylamide ccc) 444-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-y1]-piperidine-1-carboxylic acid sec-butylamide ddd) 444-(Cyc(ohexyl-cyclopropyl-carbamoy1)-thiazol-2-y11-piperidine-1-carboxylic acid tert-butylamide eee) 444-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-y11-piperidine-1-carboxylic acid propylamide fff) 444-(Cyclohexyl-cyclopropy(-carbamoy1)-thiazol-2-y1j-piperidine-1-carboxylic acid ethylamide ggg) 4-[4-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-yl]-piperidine-1-carboxylic acid cyclopentylamide hhh) 444-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-y(Fpiperidine-1-carboxylic acid isopropylamide iii) 414-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-y1]-piperidine-1-carboxylic acid pentylamide jjj) 444-(4-Hydroxy-octahydro-quinoline-1-carbonyl)-thiazol-2-A-piperidine-1-carboxylic acid 4-methoxy-benzylamide kkk) 444-(4-Hydroxy-octahydro-quinoline-1-carbonyl)-thiazol-2-y1Fpiperid me-1-carboxylic acid (4-butyl-phenyl)-amide III) 3-({444-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-01-piperid ine-1-carbonylyamino)-propion ic acid mmm) 444-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-01-piperidine-1 -carboxylic acid (4-butyl-phenyl)-amide nnn) 444-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-yll-piperidine-1-carboxylic acid 4-methoxy-benzylamide
- 19 -000) 3-({444-(Octahydro-quinoline-1-carbonyl)-thiazol-2-ylj-piperidine-1-carbonylyamino)-propionic acid ppp) 4-[4-(Octahydro-q uinoline-1-carbony1)-thiazol-2-y1]-piperidine-1-carboxylic acid (4-butyl-phenyl)-amide qqq) 444-(Octahydro-quinoline-1-carbony1)-thiazol-2-yll-piperidine-1-carboxylic acid 4-methoxy-benzylamide rrr) 3-({4-[4-(Piperidine-1-carbonyl)-thiazol-211]-piperidine-1-carbony1}-amino)-propionic acid sss) 4[4-(Piperidine-1-carbonyl)-thiazol-2-y1]-piperidine-1-carboxylic acid (4-butyl-phenyl)-amide ttt) 4[4-(Piperidine-1-carbony1)-thiazol-2-y1]-piperidine-1-carboxylic acid 4-methoxy-benzylamide uuu) 3-({414-(Cyclohexyl-methyl-carbamoy1)-thiazol-2-y1]-piperidine-1-carbonyl}amino)-propionic acid vvv) 4[4-(Cyclohexyl-methyl-carbamoy1)-thiazol-2-y1Fpiperidine-1-carboxylic acid (4-butyl-phenyl)-amide www) 444-(Cyclohexyl-methyl-carbamoy1)-thiazol-2-y11-piperidine-1-carboxylic acid 4-methoxy-benzylamide xxx) (Octahydro-quinolin-1-y1)42-(1-trifluoromethanesu)fonyl-piperidin-4-y1)-thiazol-4-yll-methanone yyy) {241-(Butane-1-sulfony1)-piperidin-4-yli-thiazol-4-y1)-(octahydro-quinolin-1-yI)-methanone zzz) (Octahydro-quinolin-1-y1)-{2-0-(propane-1-sulfonyl)-piperidin-4-y11-thiazol-4-y1}-methanone aaaa) [2-(1-Ethanesulfonyl-piperidin-4-y1)-thiazol-4-y1]-(octahyd10-quinolin-1-y1)-methanone bbbb) 2-(1-Trifluoromethanesulfonyl-piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide
- 20 -cccc) 241-(Butane-1-sulfony1)-piperidin-4-ylphiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide dddd) 241-(Propane-2-sulfony1)-piperidin-4-ylythiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide eeee) 2-[1-(Propane-1-sulfony1)-piperidin-4-ylythiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide ffff) 2-(1-Ethanesulfonyl-piperidin-4-yI)-thiazole-4-carboxylic acid cyclo-hexyl-cyclopropyl-amide gggg) (Octahydro-quino)in-1-y1)-{241 -(thiophene-2-su)fony1)-piperidin-4-y1Fthiazol-4-y1}-methanone hhhh) 2El-(Thiophene-2-sulfonyl)-piperidin-4-y11-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide iiii) 241-(4-Trifluoromethoxy-benzenesulfony))-piperidin-4-A-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide jjjj) 241-(4-Fluoro-benzenesulfonyl)-piperidin-4-y1J-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide kkkk) (Octahydro-quinolin-1-y1)-{241-(4-trifluoromethoxy-benzenesulfony1)-piperidin-4-ylphiazol-4-y!}-methanone 1111) {241-(4-Fluoro-benzenesulfonyl)-piperidin-4-y11-thiazol-4-y1}-(octahydro-quinolin-1-y1)-methanone mmmm) {241-(4-Fluoro-benzenesulfony1)-piperidin-4-y1Fthiazol-4-y11-(4-hydroxy-octahydro-quinolin-1-y1)-methanone nnnn) (4-Hydroxy-octahydro-quinolin-1-y1)42-(1-methanesulfonyl-piperidin-4-y1)-thiazol-4-yll-methanone 0000) 241-(2-Pyridin-4-yl-ethanesulfonyl)-piperidin-4-y1Fthiazole-4-carboxylic acid cyclohexyl-cyclopropyI-amide pppp) Piperidin-1-y1-{241-(2-pyridin-4-y1-ethanesu(fony1)-piperidin-4-y11-thiazol-4-y1}-methanone
- 21 -qqqq) 241-(4-Methoxy-benzenesulfony1)-piperidin-4-ylphiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide rrrr) 241-(4-tert-Butyl-benzenesulfony1)-piperidin-4-ylphiazo(e-4-carboxylic acid cyclohexyl-cyclopropyl-amide ssss) 2-(1-Methanesulfonyl-piperidin-4-y1)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide tttt) {241-(4-Methoxy-benzenesulfony1)-piperidin-4-y1Hhiazol-4-y1}-(octahydro-quinolin-1-y1)-methanone uuuu) {241-(4-tert-Butyl-benzenesulfony1)-piperidin-4-y11-thiazol-4-y1}-(octahydro-quinolin-l-y1)-methanone vvvv) [2-(1-Methanesulfonyl-piperidin-4-y1)-thiazol-4-y1]-(octahyd10-quinolin-1-y1)-methanone wwww) {2-[1-(4-Methoxy-benzenesulfony1)-piperidin-4-A-thiazol-4-y1}-piperidin- 1 -yl-methanone xxxx) {241-(4-tert-Butyl-benzenesulfony1)-piperidin-4-y1]-thiazol-4-y1}-piperidin-l-yl-methanone YYYY) [2-(1-Methanesulfonyl-piperidin-4-y1)-thiazol-4-y1]-piperidin-l-yl-methanone zzzz) 241-(4-Methoxy-benzenesulfonyl)-piperidin-4-ylj-thiazole-4-carboxylic acid cyclohexyl-methyl-amide aaaaa) 211-(4-tert-Butyl-benzenesulfony1)-piperidin-4-yll-thiazole-carboxylic acid cyclohexyl-methyl-amide bbbbb) 2-(1-Methanesulfonyl-piperidin-4-y1)-thiazole-4-carboxylic acid cyclohexyl-methyl-amide ccccc) 2-(1-Cyclohexylmethyl-piperidin-4-y1)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide ddddd) [2-(1-Cyclohexylmethyl-piperidin-4-y1)-thiazol-4-y11-(octahydro-quinolin-l-y1)-methanone
- 22 -eeeee) 2-[1-(2-Cyclohexy1-ethyl)-piperidin-4-y1)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide fffff 241-(Tetrahydro-pyran-2-ylmethyl)-piperidin-4-yll-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide ggggg) 2-(1-Cyanomethyl-piperidin-4-yI)-thiazole-4-carboxylic acid cyclo-hexyl-cyclopropyl-amide hhhhh) 2-(1-Carbamoylmethyl-piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 2-(1-Pentyl-piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide Jim) 2-(1-lsobutyl-piperidin-4-y1)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide kkkkk) 241-(3-Methyl-buty1)-piperidin-4-01-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 11111) 2-(1-Butyl-piperidin-4-yI)-thiazoIe-4-carboxylic acid cyclohexyI-cyclopropyl-amide mmmmm) {241-(2-Cyclohexyl-ethyl)-piperidin-4-ylPhiazol-4-y1Hoctahydro-quinolin-1-yI)-methanone nnnnn) (Octahydro-quinolin-1-y1)-{241-(tetrahydro-pyran-2-ylmethyl)-piperidin-4-ylphiazol-4-y1}-methanone 00000) {444-(Octahydro-quino(ine-1-carbony1)-thiazol-2-yll-piperidin-y1}-acetonitrile ppppp) 2-14-[4-(Octahydro-quinoline-1-carbony1)-thiazol-2-y1]-piperidin-l-y1}-acetamide qqqqq) (Octahydro-quinolin-1-y1)-[2-(1-pentyl-piperidin-4-y1)-thiazol-4-yll-methanone rrrrr) [2-(1-lsobutyl-piperidin-4-y1)-thiazol-4-y11-(octahydro-quinolin-1-y1)-methanone
- 23 -sssss) {241-(3-Methyl-butyp-piperidin-4-ylphiazol-4-y1Hoctahydro-quinolin-1-y1)-methanone ttttt) [2-(1-Butyl-piperidin-4-y1)-thiazol-4-y1]-(octahydro-quinolin-1-y1)-methanone and the physiologically acceptable salts, derivatives, prodrugs, solvates and stereoisomers thereof, including mixtures thereof in all ratios.
All the above generically or explicitly disclosed thiazole derivatives, in-cluding preferred subsets/embodiments of formula (I) and Compounds a) to ttttt), are hereinafter referred to as compounds of the (present) invention.
The nomenclature as used herein for defining compounds, especially the compounds according to the invention, is in general based on the rules of the IUPAC-organisation for chemical compounds and especially organic corn-pounds.
The terms indicated for explanation of the above compounds of the inven-tion always, unless indicated otherwise in the description or in the claims, have the following meanings:
The term "unsubstituted" means that the corresponding radical, group or moiety has no substituents.
The term "substituted" means that the corresponding radical, group or moiety has one or more substituents. Where a radical has a plurality of sub-stituents, and a selection of various substituents is specified, the substituents are selected independently of one another and do not need to be identical.
The terms "alkyl" or "A" as well as other groups having the prefix "alk" for the purposes of this invention refer to acyclic saturated or unsaturated hydro-carbon radicals which may be branched or straight-chain and preferably have 1 to 8 carbon atoms, i.e. C1-C8-alkanyls, C2-C8-alkenyls and C2-C8-alkynyls.
Alkenyls have at least one C-C double bond and alkynyls at least one C-C
All the above generically or explicitly disclosed thiazole derivatives, in-cluding preferred subsets/embodiments of formula (I) and Compounds a) to ttttt), are hereinafter referred to as compounds of the (present) invention.
The nomenclature as used herein for defining compounds, especially the compounds according to the invention, is in general based on the rules of the IUPAC-organisation for chemical compounds and especially organic corn-pounds.
The terms indicated for explanation of the above compounds of the inven-tion always, unless indicated otherwise in the description or in the claims, have the following meanings:
The term "unsubstituted" means that the corresponding radical, group or moiety has no substituents.
The term "substituted" means that the corresponding radical, group or moiety has one or more substituents. Where a radical has a plurality of sub-stituents, and a selection of various substituents is specified, the substituents are selected independently of one another and do not need to be identical.
The terms "alkyl" or "A" as well as other groups having the prefix "alk" for the purposes of this invention refer to acyclic saturated or unsaturated hydro-carbon radicals which may be branched or straight-chain and preferably have 1 to 8 carbon atoms, i.e. C1-C8-alkanyls, C2-C8-alkenyls and C2-C8-alkynyls.
Alkenyls have at least one C-C double bond and alkynyls at least one C-C
- 24 -triple bond. Alkynyls may additionally also have at least one C-C double bond. Examples of suitable alkyl radicals are methyl, ethyl, n-propyl, isopro-pyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, 2- or 3-methyl-pentyl, n-hexyl, 2-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-icosanyl, n-docosanyl, ethylenyl (vinyl), propenyl (-CH2CH=CH2;
-CH=CH-CH3, -C(=CH2)-CH3), butenyl, pentenyl, hexenyl, heptenyl, octenyl, octadienyl, octadecenyl, octadec-9-enyl, icosenyl, icos-11-enyl, (Z)-icos-11-enyl, docosnyl, docos-13-enyl, (Z)-docos-13-enyl, ethynyl, propynyl (-CH2-CE-CH, -CE-C-CH3), butynyl, pentynyl, hexynyl, heptynyl, octynyl. Especially preferred is C1-4-alkyl. A C1-4-alkyl radical is for example a methyl, ethyl, pro-pyl, isopropyl, butyl, isobutyl, tert-butyl.
The term "cycloalkyl" for the purposes of this invention refers to saturated and partially unsaturated non-aromatic cyclic hydrocarbon groups/radicals, having Ito 3 rings, that contain 3 to 20, preferably 3 to 12, most preferably to 8 carbon atoms. The cycloalkyl radical may also be part of a bi- or poly-cyclic system, where, for example, the cycloalkyl radical is fused to an aryl, heteroaryl or heterocyclyl radical as defined herein by any possible and de-sired ring member(s). The bonding to the compounds of the general formula (I) can be effected via any possible ring member of the cycloalkyl radical. Ex-amples of suitable cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl and cyclooctadienyl. Especially preferred are C3-C9-cycloalkyl and C4-05-cycloalkyl. A C4-C8-cycloalkyl radical is for example a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
The term "heterocycly1" for the purposes of this invention refers to a mono- or polycyclic system of 3 to 20, preferably 5 or 6 to 14 ring atoms comprising carbon atoms and 1, 2, 3, 4, or 5 heteroatoms, in particular nitro-gen, oxygen and/or sulfur which are identical or different. The cyclic system may be saturated, mono- or polyunsaturated but may not be aromatic. In the case of a cyclic system consisting of at least two rings the rings may be fused
-CH=CH-CH3, -C(=CH2)-CH3), butenyl, pentenyl, hexenyl, heptenyl, octenyl, octadienyl, octadecenyl, octadec-9-enyl, icosenyl, icos-11-enyl, (Z)-icos-11-enyl, docosnyl, docos-13-enyl, (Z)-docos-13-enyl, ethynyl, propynyl (-CH2-CE-CH, -CE-C-CH3), butynyl, pentynyl, hexynyl, heptynyl, octynyl. Especially preferred is C1-4-alkyl. A C1-4-alkyl radical is for example a methyl, ethyl, pro-pyl, isopropyl, butyl, isobutyl, tert-butyl.
The term "cycloalkyl" for the purposes of this invention refers to saturated and partially unsaturated non-aromatic cyclic hydrocarbon groups/radicals, having Ito 3 rings, that contain 3 to 20, preferably 3 to 12, most preferably to 8 carbon atoms. The cycloalkyl radical may also be part of a bi- or poly-cyclic system, where, for example, the cycloalkyl radical is fused to an aryl, heteroaryl or heterocyclyl radical as defined herein by any possible and de-sired ring member(s). The bonding to the compounds of the general formula (I) can be effected via any possible ring member of the cycloalkyl radical. Ex-amples of suitable cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl and cyclooctadienyl. Especially preferred are C3-C9-cycloalkyl and C4-05-cycloalkyl. A C4-C8-cycloalkyl radical is for example a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
The term "heterocycly1" for the purposes of this invention refers to a mono- or polycyclic system of 3 to 20, preferably 5 or 6 to 14 ring atoms comprising carbon atoms and 1, 2, 3, 4, or 5 heteroatoms, in particular nitro-gen, oxygen and/or sulfur which are identical or different. The cyclic system may be saturated, mono- or polyunsaturated but may not be aromatic. In the case of a cyclic system consisting of at least two rings the rings may be fused
- 25 -or Spiro- or otherwise connected. Such "heterocycly1" radicals can be linked via any ring member. The term "heterocycly1" also includes systems in which the heterocycle is part of a bi- or polycyclic saturated, partially unsaturated and/or aromatic system, such as where the heterocycle is fused to an "aryl", "cycloalkyl", "heteroaryl" or "heterocycly1" group as defined herein via any de-sired and possible ring member of the heterocycyl radical. The bonding to the compounds of the general formula (I) can be effected via any possible ring member of the heterocycyl radical. Examples of suitable "heterocycly1" radi-cals are pyrrolidinyl, thiapyrrolidinyl, piperidinyl, piperazinyl, oxapiperazinyl, oxapiperidinyl, oxadiazolyl, tetrahydrofuryl, imidazolidinyl, thiazolidinyl, tetra-hydropyranyl, nnorpholinyl, tetrahydrothiophenyl, dihydropyranyl.
The term "aryl" for the purposes of this invention refers to a mono- or polycyclic aromatic hydrocarbon systems having 3 to 14, preferably 5 to 14, more preferably 6 to 10 carbon atoms. The term "aryl" also includes systems in which the aromatic cycle is part of a bi- or polycyclic saturated, partially unsaturated and/or aromatic system, such as where the aromatic cycle is fused to an "aryl", "cycloalkyl", "heteroaryl" or "heterocycly1" group as defined herein via any desired and possible ring member of the aryl radical. The bonding to the compounds of the general formula (I) can be effected via any possible ring member of the aryl radical. Examples of suitable "aryl" radicals are phenyl, biphenyl, naphthyl, 1-naphthyl, 2-naphthyl and anthracenyl, but likewise indanyl, indenyl, or 1,2,3,4-tetrahydronaphthyl. The most preferred aryl is phenyl.
The term "heteroaryl" for the purposes of this invention refers to a 3 to 15, preferably 5 to 14, more preferably 5-, 6- or 7-membered mono- or polycyclic aromatic hydrocarbon radical which comprises at least 1, where appropriate also 2, 3, 4 or 5 heteroatoms, preferably nitrogen, oxygen and/or sulfur, where the heteroatoms are identical or different. The number of nitrogen at-oms is preferably 0, 1, 2, or 3, and that of the oxygen and sulfur atoms is in-dependently 0 or 1. The term "heteroaryl" also includes systems in which the aromatic cycle is part of a bi- or polycyclic saturated, partially unsaturated
The term "aryl" for the purposes of this invention refers to a mono- or polycyclic aromatic hydrocarbon systems having 3 to 14, preferably 5 to 14, more preferably 6 to 10 carbon atoms. The term "aryl" also includes systems in which the aromatic cycle is part of a bi- or polycyclic saturated, partially unsaturated and/or aromatic system, such as where the aromatic cycle is fused to an "aryl", "cycloalkyl", "heteroaryl" or "heterocycly1" group as defined herein via any desired and possible ring member of the aryl radical. The bonding to the compounds of the general formula (I) can be effected via any possible ring member of the aryl radical. Examples of suitable "aryl" radicals are phenyl, biphenyl, naphthyl, 1-naphthyl, 2-naphthyl and anthracenyl, but likewise indanyl, indenyl, or 1,2,3,4-tetrahydronaphthyl. The most preferred aryl is phenyl.
The term "heteroaryl" for the purposes of this invention refers to a 3 to 15, preferably 5 to 14, more preferably 5-, 6- or 7-membered mono- or polycyclic aromatic hydrocarbon radical which comprises at least 1, where appropriate also 2, 3, 4 or 5 heteroatoms, preferably nitrogen, oxygen and/or sulfur, where the heteroatoms are identical or different. The number of nitrogen at-oms is preferably 0, 1, 2, or 3, and that of the oxygen and sulfur atoms is in-dependently 0 or 1. The term "heteroaryl" also includes systems in which the aromatic cycle is part of a bi- or polycyclic saturated, partially unsaturated
- 26 -and/or aromatic system, such as where the aromatic cycle is fused to an "aryl", "cycloalkyl", "heteroaryl" or "heterocyclyl" group as defined herein via any desired and possible ring member of the heteroaryl radical. The bonding to the compounds of the general formula (I) can be effected via any possible ring member of the heteroaryl radical. Examples of suitable "heteroaryl" are pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, qui-nolinyl, isoquinolinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, phthalazinyl, in-dazolyl, indolizinyl, quinoxalinyl, quinazolinyl, pteridinyl, carbazolyl, phenazinyl, phenoxazinyl, phenothiazinyl, acridinyl.
For the purposes of the present invention, the terms "alkyl-cycloalkyl", "cycloalkylalkyl", "alkyl-heterocyclyl", "heterocyclylalkyl", "alkyl-aryl", "arylal-kyl", "alkyl-heteroaryl" and "heteroarylalkyl" mean that alkyl, cycloalkyl, het-erocycl, aryl and heteroaryl are each as defined above, and the cycloalkyl, heterocyclyl, aryl and heteroaryl radical is bonded to the compounds of the general formula (I) via an alkyl radical, preferably Ci-C9-alkyl radical, more preferably C1-C4-alkyl radical.
The term "alkyloxy" or "alkoxy" for the purposes of this invention refers to an alkyl radical according to above definition that is attached to an oxygen atom. The attachment to the compounds of the general formula (I) is via the oxygen atom. Examples are methoxy, ethoxy and n-propyloxy, propoxy, iso-propoxy. Preferred is "C1-C4-alkyloxy" having the indicated number of carbon atoms.
The term "cycloalkyloxy" or "cycloalkoxy" for the purposes of this invention refers to a cycloalkyl radical according to above definition that is attached to an oxygen atom. The attachment to the compounds of the general formula (I) is via the oxygen atom. Examples are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy. Preferred is "C3-C9cycloalkyloxy" having the indicated number of carbon atoms.
The term "heterocyclyloxy" for the purposes of this invention refers to a heterocyclyl radical according to above definition that is attached to an oxy-
For the purposes of the present invention, the terms "alkyl-cycloalkyl", "cycloalkylalkyl", "alkyl-heterocyclyl", "heterocyclylalkyl", "alkyl-aryl", "arylal-kyl", "alkyl-heteroaryl" and "heteroarylalkyl" mean that alkyl, cycloalkyl, het-erocycl, aryl and heteroaryl are each as defined above, and the cycloalkyl, heterocyclyl, aryl and heteroaryl radical is bonded to the compounds of the general formula (I) via an alkyl radical, preferably Ci-C9-alkyl radical, more preferably C1-C4-alkyl radical.
The term "alkyloxy" or "alkoxy" for the purposes of this invention refers to an alkyl radical according to above definition that is attached to an oxygen atom. The attachment to the compounds of the general formula (I) is via the oxygen atom. Examples are methoxy, ethoxy and n-propyloxy, propoxy, iso-propoxy. Preferred is "C1-C4-alkyloxy" having the indicated number of carbon atoms.
The term "cycloalkyloxy" or "cycloalkoxy" for the purposes of this invention refers to a cycloalkyl radical according to above definition that is attached to an oxygen atom. The attachment to the compounds of the general formula (I) is via the oxygen atom. Examples are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy. Preferred is "C3-C9cycloalkyloxy" having the indicated number of carbon atoms.
The term "heterocyclyloxy" for the purposes of this invention refers to a heterocyclyl radical according to above definition that is attached to an oxy-
- 27 -gen atom. The attachment to the compounds of the general formula (I) is via the oxygen atom. Examples are pyrrolidinyloxy, thiapyrrolidinyloxy, piperid-inyloxy, piperazinyloxy.
The term "aryloxy" for the purposes of this invention refers to an aryl radi-cal according to above definition that is attached to an oxygen atom. The at-tachment to the compounds of the general formula (I) is via the oxygen atom.
Examples are phenyloxjt, 2-naphthyloxy, 1-naphthyloxy, biphenyloxy, indany-loxy. Preferred is phenyloxy.
The term "heteroaryloxy" for the purposes of this invention refers to a het-eroaryl radical according to above definition that is attached to an oxygen atom. The attachment to the compounds of the general formula (I) is via the oxygen atom. Examples are pyrrolyloxy, thienyloxy, furyloxy, imidazolyloxy, thiazolyloxy.
The term "halogen", "halogen atom", "halogen substituent" or "Hal" for the purposes of this invention refers to one or, where appropriate, a plurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl, chloro), or iodine (I, iodo) atoms. The designations "dihalogen", "trihalogen" and "perhalogen" re-fer respectively to two, three and four substituents, where each substituent can be selected independently from the group consisting of fluorine, chlorine, bromine and iodine. "Halogen" preferably means a fluorine, chlorine or bro-mine atom. Fluorine is most preferred, when the halogens are substituted on an alkyl (haloalkyl) or alkoxy group (e.g. CF3 and CF30).
The term "hydroxyl" means an OH group.
The term "composition", as in pharmaceutical composition, for the pur-poses of this invention is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reac-tions or interactions of one or more of the ingredients. Accordingly, the phar-maceutical compositions of the present invention encompass any composi-
The term "aryloxy" for the purposes of this invention refers to an aryl radi-cal according to above definition that is attached to an oxygen atom. The at-tachment to the compounds of the general formula (I) is via the oxygen atom.
Examples are phenyloxjt, 2-naphthyloxy, 1-naphthyloxy, biphenyloxy, indany-loxy. Preferred is phenyloxy.
The term "heteroaryloxy" for the purposes of this invention refers to a het-eroaryl radical according to above definition that is attached to an oxygen atom. The attachment to the compounds of the general formula (I) is via the oxygen atom. Examples are pyrrolyloxy, thienyloxy, furyloxy, imidazolyloxy, thiazolyloxy.
The term "halogen", "halogen atom", "halogen substituent" or "Hal" for the purposes of this invention refers to one or, where appropriate, a plurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl, chloro), or iodine (I, iodo) atoms. The designations "dihalogen", "trihalogen" and "perhalogen" re-fer respectively to two, three and four substituents, where each substituent can be selected independently from the group consisting of fluorine, chlorine, bromine and iodine. "Halogen" preferably means a fluorine, chlorine or bro-mine atom. Fluorine is most preferred, when the halogens are substituted on an alkyl (haloalkyl) or alkoxy group (e.g. CF3 and CF30).
The term "hydroxyl" means an OH group.
The term "composition", as in pharmaceutical composition, for the pur-poses of this invention is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reac-tions or interactions of one or more of the ingredients. Accordingly, the phar-maceutical compositions of the present invention encompass any composi-
- 28 -tion made by admixing a compound of the present invention and a pharma-ceutically acceptable carrier.
The terms "administration of' and "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individualist need.
As used herein, the term "effective amount" refers to any amount of a drug or pharmaceutical agent that will elicit the biological or medical re-sponse of a tissue, system, animal or human that is being sought, for in-stance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
All stereoisomers of the compounds of the invention are contemplated, ei-ther in a mixture or in pure or substantially pure form. The compounds of the invention can have asymmetric centers at any of the carbon atoms. Conse-quently, they can exist in the form of their racemates, in the form of the pure enantiomers and/or diastereomers or in the form of mixtures of these enanti-omers and/or diastereomers. The mixtures may have any desired mixing ra-tio of the stereoisomers.
Thus, for example, the compounds of the invention which have one or more centers of chirality and which occur as racemates or as diastereomer mixtures can be fractionated by methods known per se into their optical pure isomers, i.e. enantiomers or diastereomers. The separation of the com-pounds of the invention can take place by column separation on chiral or nonchiral phases or by recrystallization from an optionally optically active sol-vent or with use of an optically active acid or base or by derivatization with an optically active reagent such as, for example, an optically active alcohol, and
The terms "administration of' and "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individualist need.
As used herein, the term "effective amount" refers to any amount of a drug or pharmaceutical agent that will elicit the biological or medical re-sponse of a tissue, system, animal or human that is being sought, for in-stance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
All stereoisomers of the compounds of the invention are contemplated, ei-ther in a mixture or in pure or substantially pure form. The compounds of the invention can have asymmetric centers at any of the carbon atoms. Conse-quently, they can exist in the form of their racemates, in the form of the pure enantiomers and/or diastereomers or in the form of mixtures of these enanti-omers and/or diastereomers. The mixtures may have any desired mixing ra-tio of the stereoisomers.
Thus, for example, the compounds of the invention which have one or more centers of chirality and which occur as racemates or as diastereomer mixtures can be fractionated by methods known per se into their optical pure isomers, i.e. enantiomers or diastereomers. The separation of the com-pounds of the invention can take place by column separation on chiral or nonchiral phases or by recrystallization from an optionally optically active sol-vent or with use of an optically active acid or base or by derivatization with an optically active reagent such as, for example, an optically active alcohol, and
- 29 -subsequent elimination of the radical.
The compounds of the invention may be present in the form of their dou-ble bond isomers as "pure" E or Z isomers, or in the form of mixtures of these double bond isomers.
Where possible, the compounds of the invention may be in the form of the tautomers, such as keto-enol tautomers.
It is likewise possible for the compounds of the invention to be in the form of any desired prodrugs such as, for example, esters, carbonates, car-bamates, ureas, amides or phosphates, in which cases the actually biologi-cally active form is released only through metabolism. Any compound that can be converted in vivo to provide the bioactive agent (i.e. compounds of the invention) is a prodrug within the scope and spirit of the invention.
Various forms of prodrugs are well known in the art and are described for instance in:
(i) Wermuth CG et al., Chapter 31: 671-696, The Practice of Medicinal Chemis-try, Academic Press 1996;
(ii) Bundgaard H, Design of Prodrugs, Elsevier 1985; and (iii) Bundgaard H, Chapter 5: 131-191, A Textbook of Drug Design and Devel-opment, Harwood Academic Publishers 1991.
It is further known that chemical substances are converted in the body into metabolites which may where appropriate likewise elicit the desired bio-logical effect - in some circumstances even in more pronounced form.
Any biologically active compound that was converted in vivo by metabo-lism from any of the compounds of the invention is a metabolite within the scope and spirit of the invention.
The compounds of the invention can, if they have a sufficiently basic group such as, for example, a secondary or tertiary amine, be converted with
The compounds of the invention may be present in the form of their dou-ble bond isomers as "pure" E or Z isomers, or in the form of mixtures of these double bond isomers.
Where possible, the compounds of the invention may be in the form of the tautomers, such as keto-enol tautomers.
It is likewise possible for the compounds of the invention to be in the form of any desired prodrugs such as, for example, esters, carbonates, car-bamates, ureas, amides or phosphates, in which cases the actually biologi-cally active form is released only through metabolism. Any compound that can be converted in vivo to provide the bioactive agent (i.e. compounds of the invention) is a prodrug within the scope and spirit of the invention.
Various forms of prodrugs are well known in the art and are described for instance in:
(i) Wermuth CG et al., Chapter 31: 671-696, The Practice of Medicinal Chemis-try, Academic Press 1996;
(ii) Bundgaard H, Design of Prodrugs, Elsevier 1985; and (iii) Bundgaard H, Chapter 5: 131-191, A Textbook of Drug Design and Devel-opment, Harwood Academic Publishers 1991.
It is further known that chemical substances are converted in the body into metabolites which may where appropriate likewise elicit the desired bio-logical effect - in some circumstances even in more pronounced form.
Any biologically active compound that was converted in vivo by metabo-lism from any of the compounds of the invention is a metabolite within the scope and spirit of the invention.
The compounds of the invention can, if they have a sufficiently basic group such as, for example, a secondary or tertiary amine, be converted with
- 30 -inorganic and organic acids into salts. The pharmaceutically acceptable salts of the compounds of the invention are preferably formed with hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, phosphoric acid, methanesul-fonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, sul-foacetic acid, trifluoroacetic acid, oxalic acid, malonic acid, maleic acid, suc-cinic acid, tartaric acid, racemic acid, malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid or aspartic acid. The salts which are formed are, inter alia, hydrochlorides, chlorided, hydrobromides, bromides, iodides, sul-fates, phosphates, methanesulfonates, tosylates, carbonates, bicarbonates, formates, acetates, sulfoacetates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embonates, mandelates, fumarates, lactates, citrates, glutarates, stearates, aspartates and glutamates. The stoichiometry of the salts formed from the compounds of the invention may moreover be an integral or non-integral multiple of one.
The compounds of the invention can, if they contain a sufficiently acidic group such as, for example, the carboxy, sulfonic acid, phosphoric acid or a phenolic group, be converted with inorganic and organic bases into their physiologically tolerated salts. Examples of suitable inorganic bases are am-monium, sodium hydroxide, potassium hydroxide, calcium hydroxide, and of organic bases are ethanolamine, diethanolamine, triethanolamine, ethyl-enediamine, t-butylamine, t-octylamine, dehydroabietylamine, cyclohexyl-amine, dibenzylethylene-diamine and lysine. The stoichiometry of the salts formed from the compounds of the invention can moreover be an integral or non-integral multiple of one.
It is likewise possible for the compounds of the invention to be in the form of their solvates and, in particular, hydrates which can be obtained for exam-ple by crystallization from a solvent or from aqueous solution. It is moreover possible for one, two, three or any number of solvate or water molecules to combine with the compounds of the invention to give solvates and hydrates.
By the term "solvate" is meant a hydrate, an alcoholate, or other solvate
The compounds of the invention can, if they contain a sufficiently acidic group such as, for example, the carboxy, sulfonic acid, phosphoric acid or a phenolic group, be converted with inorganic and organic bases into their physiologically tolerated salts. Examples of suitable inorganic bases are am-monium, sodium hydroxide, potassium hydroxide, calcium hydroxide, and of organic bases are ethanolamine, diethanolamine, triethanolamine, ethyl-enediamine, t-butylamine, t-octylamine, dehydroabietylamine, cyclohexyl-amine, dibenzylethylene-diamine and lysine. The stoichiometry of the salts formed from the compounds of the invention can moreover be an integral or non-integral multiple of one.
It is likewise possible for the compounds of the invention to be in the form of their solvates and, in particular, hydrates which can be obtained for exam-ple by crystallization from a solvent or from aqueous solution. It is moreover possible for one, two, three or any number of solvate or water molecules to combine with the compounds of the invention to give solvates and hydrates.
By the term "solvate" is meant a hydrate, an alcoholate, or other solvate
- 31 -of crystallization.
It is known that chemical substances form solids which exist in different order states which are referred to as polymorphic forms or modifications. The various modifications of a polymorphic substance may differ greatly in their physical properties. The compounds of the invention can exist in various po-lymorphic forms and certain modifications may moreover be metastable. All these polymorphic forms of the compounds are to be regarded as belonging to the invention.
The compounds can be prepared by general method A, B and C shown below. In all preparative methods, all starting material is known or may easily be prepared from known starting materials.
o o o A.--\
(3)-LNI Br 0 -1'ONO
+
--..._,.....,..---,,f.S i0 1-=õ,,,ir S ...õ.õ)-H.r 0 ,õ,___., N
L.,..õ,,'-,T,.<,=Nµ 40 S OH
R1 õ R2 HN
N
0 -----'" =-...,õ7=...fNi/
S -2 \ N ¨R 1 /
Method A ¨ Coupling of piperazin to 1 eq acyl chloride or carboxyl chlo-ride in a polar solvent at -20 to 50 C, most preferably 0 to 20 C
It is known that chemical substances form solids which exist in different order states which are referred to as polymorphic forms or modifications. The various modifications of a polymorphic substance may differ greatly in their physical properties. The compounds of the invention can exist in various po-lymorphic forms and certain modifications may moreover be metastable. All these polymorphic forms of the compounds are to be regarded as belonging to the invention.
The compounds can be prepared by general method A, B and C shown below. In all preparative methods, all starting material is known or may easily be prepared from known starting materials.
o o o A.--\
(3)-LNI Br 0 -1'ONO
+
--..._,.....,..---,,f.S i0 1-=õ,,,ir S ...õ.õ)-H.r 0 ,õ,___., N
L.,..õ,,'-,T,.<,=Nµ 40 S OH
R1 õ R2 HN
N
0 -----'" =-...,õ7=...fNi/
S -2 \ N ¨R 1 /
Method A ¨ Coupling of piperazin to 1 eq acyl chloride or carboxyl chlo-ride in a polar solvent at -20 to 50 C, most preferably 0 to 20 C
- 32 -HN
\N-R1 S-2 \N-R1 HN )1, /R3 R3 II
\N-R1 S-2 \N-R1 Method B ¨ Coupling of piperazin to 1 eq isocyanate in a polar solvent at -20 to 50 C, most preferably 0 to 20 C
HN
R3,N
\N-R1 \N-R1 /
Method C ¨ Coupling of piperazin to 1 eq sulfonyl chloride in a polar sol-vent at -20 to 50 C, most preferably 0 to 20 C
00o II 11,, HN S, \\.1:23 R3 N
\N-R1
\N-R1 S-2 \N-R1 HN )1, /R3 R3 II
\N-R1 S-2 \N-R1 Method B ¨ Coupling of piperazin to 1 eq isocyanate in a polar solvent at -20 to 50 C, most preferably 0 to 20 C
HN
R3,N
\N-R1 \N-R1 /
Method C ¨ Coupling of piperazin to 1 eq sulfonyl chloride in a polar sol-vent at -20 to 50 C, most preferably 0 to 20 C
00o II 11,, HN S, \\.1:23 R3 N
\N-R1
- 33 -Method D ¨ Coupling of piperazin to 1 eq bromide in a polar solvent at -200 to 50 C, most preferably 0 to 20 C
HN
BrR3 R3".N/\, S
The compounds of the formula (I) and also the starting materials for their preparation are, are prepared by methods as described in the examples or by methods known per se, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.
The starting materials for the claimed process may, if desired, also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the formula (I).
On the other hand, it is possible to carry out the reaction stepwise.
Preferably, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or di-chloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THE) or dioxane; glycol ethers, such as ethylene gly-col monomethyl or monoethyl ether or ethylene glycol dimethyl ether (di-glyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methyl pyrrolidinone
HN
BrR3 R3".N/\, S
The compounds of the formula (I) and also the starting materials for their preparation are, are prepared by methods as described in the examples or by methods known per se, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.
The starting materials for the claimed process may, if desired, also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the formula (I).
On the other hand, it is possible to carry out the reaction stepwise.
Preferably, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or di-chloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THE) or dioxane; glycol ethers, such as ethylene gly-col monomethyl or monoethyl ether or ethylene glycol dimethyl ether (di-glyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methyl pyrrolidinone
- 34 -(NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMS0); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents or mixtures with water.
Polar solvents are in general preferred. Examples for suitable polar solvents are chlorinated hydrocarbons, alcohols, glycol ethers, nitriles, amides and sulfoxides or mixtures thereof. More preferred are amides, especially di-methylformamide (DMF).
As stated above, the reaction temperature is between about -100 C and 300 C, depending on the reaction step and the conditions used.
Reaction times are generally in the range between some minutes and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily deter-minable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 min and 48 his.
A base of the formula (I) can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in a preferably inert solvent, such as ethanol, followed by evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, it is possible to use inorganic ac-ids, for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydro-halic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as, for example, orthophosphoric acid, sulfamic acid, furthermore or-ganic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or hetero-cyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for exam-ple formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, de-canoic acid, hexadecanoic acid, octadecanoic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lac-tic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nico-tinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic
Polar solvents are in general preferred. Examples for suitable polar solvents are chlorinated hydrocarbons, alcohols, glycol ethers, nitriles, amides and sulfoxides or mixtures thereof. More preferred are amides, especially di-methylformamide (DMF).
As stated above, the reaction temperature is between about -100 C and 300 C, depending on the reaction step and the conditions used.
Reaction times are generally in the range between some minutes and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily deter-minable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 min and 48 his.
A base of the formula (I) can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in a preferably inert solvent, such as ethanol, followed by evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, it is possible to use inorganic ac-ids, for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydro-halic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as, for example, orthophosphoric acid, sulfamic acid, furthermore or-ganic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or hetero-cyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for exam-ple formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, de-canoic acid, hexadecanoic acid, octadecanoic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lac-tic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nico-tinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic
- 35 -acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylic acid, p-toluenesulfonic acid, glycolic acid, em-bonic acid, chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, glyoxylic acid, palmitic acid, parachlorophenoxyisobutyric acid, cyclohexane-carboxylic acid, glucose 1-phosphate, naphthalenemono- and -disulfonic ac-ids or laurylsulfuric acid.
Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify the compounds of the formula (I).
On the other hand, compounds of the formula (1) can be converted into the corresponding metal salts, in particular alkali metal salts or alkaline earth metal salts, or into the corresponding ammonium salts, using bases (for ex-ample sodium hydroxide, potassium hydroxide, sodium carbonate or potas-sium carbonate). Suitable salts are furthermore substituted ammonium salts, for example the dimethyl-, diethyl- and diisopropylammonium salts, mono-ethanol-, diethanol- and diisopropanolammonium salts, cyclohexyl- and dicy-clohexylammonium salts, dibenzylethylenediammonium salts, furthermore, for example, salts with arginine or lysine.
If desired, the free bases of the formula (I) can be liberated from their salts by treatment with strong bases, such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, so long as no further acidic groups are present in the molecule. In the cases where the com-pounds of the formula (I) have free acid groups, salt formation can likewise be achieved by treatment with bases. Suitable bases are alkali metal hydrox-ides, alkaline earth metal hydroxides or organic bases in the form of primary, secondary or tertiary amines.
Every reaction step described herein can optionally be followed by one or more working up procedures and/or isolating procedures. Suitable such pro-cedures are known in the art, for example from standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart). Examples for such procedures
Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify the compounds of the formula (I).
On the other hand, compounds of the formula (1) can be converted into the corresponding metal salts, in particular alkali metal salts or alkaline earth metal salts, or into the corresponding ammonium salts, using bases (for ex-ample sodium hydroxide, potassium hydroxide, sodium carbonate or potas-sium carbonate). Suitable salts are furthermore substituted ammonium salts, for example the dimethyl-, diethyl- and diisopropylammonium salts, mono-ethanol-, diethanol- and diisopropanolammonium salts, cyclohexyl- and dicy-clohexylammonium salts, dibenzylethylenediammonium salts, furthermore, for example, salts with arginine or lysine.
If desired, the free bases of the formula (I) can be liberated from their salts by treatment with strong bases, such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, so long as no further acidic groups are present in the molecule. In the cases where the com-pounds of the formula (I) have free acid groups, salt formation can likewise be achieved by treatment with bases. Suitable bases are alkali metal hydrox-ides, alkaline earth metal hydroxides or organic bases in the form of primary, secondary or tertiary amines.
Every reaction step described herein can optionally be followed by one or more working up procedures and/or isolating procedures. Suitable such pro-cedures are known in the art, for example from standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart). Examples for such procedures
- 36 -include, but are not limited to evaporating a solvent, distilling, crystallization, fractionised crystallization, extraction procedures, washing procedures, di-gesting procedures, filtration procedures, chromatography, chromatography by HPLC and drying procedures, especially drying procedures in vacuo and/or elevated temperature.
The object of the present invention has surprisingly been solved in an-other aspect by providing a process of manufacturing a compound of the in-vention, comprising the steps:
a)4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester is reacted with ethyl bromopyruvate to yield 4-(2-ethoxycarbony1-2-oxo-ethylsulanylcarbonimidoy1)-piperidine-1-carboxylic acid tert-butyl ester ("addi-tion reaction"), and 13r0 0 b)4-(2-ethoxycarbony1-2-oxo-ethylsulanylcarbonimidoy1)-piperidine-1-carboxylic acid tert-butyl ester is converted into 4-(4-ethoxycarbonyl-thiazol-2-y1)-piperidine-1-carboxylic acid ter-butyl ester ("cyclization"), and 2t, c)444-ethoxycarbonyl-thiazol-2-y1)-piperidine-1-carboxylic acid ter-butyl ester is reacted with an acid to yield 4-(4-carboxy-thiazol-2-y1)-piperidine-1-carboxylic acid ter-butyl ester ("acidification 1"), and
The object of the present invention has surprisingly been solved in an-other aspect by providing a process of manufacturing a compound of the in-vention, comprising the steps:
a)4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester is reacted with ethyl bromopyruvate to yield 4-(2-ethoxycarbony1-2-oxo-ethylsulanylcarbonimidoy1)-piperidine-1-carboxylic acid tert-butyl ester ("addi-tion reaction"), and 13r0 0 b)4-(2-ethoxycarbony1-2-oxo-ethylsulanylcarbonimidoy1)-piperidine-1-carboxylic acid tert-butyl ester is converted into 4-(4-ethoxycarbonyl-thiazol-2-y1)-piperidine-1-carboxylic acid ter-butyl ester ("cyclization"), and 2t, c)444-ethoxycarbonyl-thiazol-2-y1)-piperidine-1-carboxylic acid ter-butyl ester is reacted with an acid to yield 4-(4-carboxy-thiazol-2-y1)-piperidine-1-carboxylic acid ter-butyl ester ("acidification 1"), and
- 37 -o)LN
(DjLN
\OH
S
d)4-(4-carboxy-thiazol-2-y1)-piperidine-1-carboxylic acid ter-butyl ester is reacted with R1-NH-R2, where R1, R2 have the meaning as defined above, to yield 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine-1-carboxylic acid ter-butyl es-ter ("amidation"), and Lc \..N\ _11 - -S OH
e)4-{4-(R1R2N-carbonyl)-thiazol-2-y1}-piperidine-1-carboxylic acid ter-butyl ester is reacted with an acid to yield 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine ("acidification 2"), and A HN
N
f1) 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine is reacted with acyl chloride to yield 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine-1-carbonyl-R3 ("acyla-tion"), where R3 has the meaning as defined above, or HN
CI)R3 R3)LN
s N-R1 S-2 \N-R1
(DjLN
\OH
S
d)4-(4-carboxy-thiazol-2-y1)-piperidine-1-carboxylic acid ter-butyl ester is reacted with R1-NH-R2, where R1, R2 have the meaning as defined above, to yield 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine-1-carboxylic acid ter-butyl es-ter ("amidation"), and Lc \..N\ _11 - -S OH
e)4-{4-(R1R2N-carbonyl)-thiazol-2-y1}-piperidine-1-carboxylic acid ter-butyl ester is reacted with an acid to yield 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine ("acidification 2"), and A HN
N
f1) 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine is reacted with acyl chloride to yield 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine-1-carbonyl-R3 ("acyla-tion"), where R3 has the meaning as defined above, or HN
CI)R3 R3)LN
s N-R1 S-2 \N-R1
- 38 -f2) 4-{4-(R1R2N-carbonyl)-thiazol-2-y1}-piperidine is reacted with isocyanate to yield 4-{4-(R1R2N-carbony1)-thiazol-2-yl}-piperidine-1-carbamoyl-R3 ("car-bamoylation"), where R3 has the meaning as defined above, or N
,, \ 0 \N¨R1 f3) 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine is reacted with sulfonyl chlo-ride to yield 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine-1-sulfonyl-R3 ("sulfonylation"), where R3 has the meaning as defined above, or II 11,9 HNõS., CI \\R3 R3 N
s N¨R1 N¨R1 f4) 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine is reacted with carboxy-chloride to yield 4-{4-(R1R2N-carbony1)-thiazol-2-yl}-piperidine-1-carboxyl-R3 ("carboxylation"), where R3 has the meaning as defined above, or HN
/<0 S N¨R1 f5) 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine is reacted with a bromide to yield 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine-1-R3 ("alkylation"), where R3 has the meaning as defined above.
S \N¨R1
,, \ 0 \N¨R1 f3) 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine is reacted with sulfonyl chlo-ride to yield 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine-1-sulfonyl-R3 ("sulfonylation"), where R3 has the meaning as defined above, or II 11,9 HNõS., CI \\R3 R3 N
s N¨R1 N¨R1 f4) 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine is reacted with carboxy-chloride to yield 4-{4-(R1R2N-carbony1)-thiazol-2-yl}-piperidine-1-carboxyl-R3 ("carboxylation"), where R3 has the meaning as defined above, or HN
/<0 S N¨R1 f5) 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine is reacted with a bromide to yield 4-{4-(R1R2N-carbony1)-thiazol-2-y1}-piperidine-1-R3 ("alkylation"), where R3 has the meaning as defined above.
S \N¨R1
- 39 -The compounds of the invention are surprisingly characterized by a strong and/or selective inhibition of 11-0-HSD-1 enzyme.
Due to their surprisingly strong and/or selective enzyme inhibition, the compounds of the invention can be advantageously administered at lower doses compared to other less potent or selective inhibitors of the prior art while still achieving equivalent or even superior desired biological effects.
In addition, such a dose reduction may advantageously lead to less or even no medicinal adverse effects. Further, the high inhibition selectivity of the com-pounds of the invention may translate into a decrease of undesired side ef-fects on its own regardless of the dose applied.
The compounds of the invention are selective inhibitors of the 11-13-HSD-1 enzyme. Thus, the present invention relates to the use of the compounds of the present invention for inhibiting the reductase activity of 11-13-hydroxysteroid dehydrogenase-1, which is responsible for the conversion of cortisone to cortisol.
The compounds of the invention being 11-0-HSD-1 inhibitors generally have an inhibition constant IC50 of less than about 500 nM, and preferably less than about 100 nM. Generally, the IC50 ratio 11-p-HSD-2 to 11-p-HSD-1 of a compound of the invention is at least about two or more, and preferably about ten or greater. Even more preferred are compounds with an IC50 ratio for 11-p-HSD-2 to 11-p-HSD-1 of about 20 or greater. For example, com-pounds of the present invention ideally demonstrate an inhibition constant IC50 against 11-0-HSD-2 greater than about 1000 nM, and preferably greater than 5000 nM.
The present invention includes the use of an 11-p-HSD-1 inhibitor for the treatment, control, amelioration, prevention, delaying the onset of or reducing the risk of developing physiological and pathophysiological conditions that are described herein, as mediated by excess or uncontrolled amounts of cor-
Due to their surprisingly strong and/or selective enzyme inhibition, the compounds of the invention can be advantageously administered at lower doses compared to other less potent or selective inhibitors of the prior art while still achieving equivalent or even superior desired biological effects.
In addition, such a dose reduction may advantageously lead to less or even no medicinal adverse effects. Further, the high inhibition selectivity of the com-pounds of the invention may translate into a decrease of undesired side ef-fects on its own regardless of the dose applied.
The compounds of the invention are selective inhibitors of the 11-13-HSD-1 enzyme. Thus, the present invention relates to the use of the compounds of the present invention for inhibiting the reductase activity of 11-13-hydroxysteroid dehydrogenase-1, which is responsible for the conversion of cortisone to cortisol.
The compounds of the invention being 11-0-HSD-1 inhibitors generally have an inhibition constant IC50 of less than about 500 nM, and preferably less than about 100 nM. Generally, the IC50 ratio 11-p-HSD-2 to 11-p-HSD-1 of a compound of the invention is at least about two or more, and preferably about ten or greater. Even more preferred are compounds with an IC50 ratio for 11-p-HSD-2 to 11-p-HSD-1 of about 20 or greater. For example, com-pounds of the present invention ideally demonstrate an inhibition constant IC50 against 11-0-HSD-2 greater than about 1000 nM, and preferably greater than 5000 nM.
The present invention includes the use of an 11-p-HSD-1 inhibitor for the treatment, control, amelioration, prevention, delaying the onset of or reducing the risk of developing physiological and pathophysiological conditions that are described herein, as mediated by excess or uncontrolled amounts of cor-
- 40 -tisol and/or other corticosteroids in a mammalian patient, particularly a hu-man, by the administration of an effective amount of a compound of the in-vention or a pharmaceutically acceptable salt or solvate thereof. Inhibition of 11-p-HSD-1 enzyme limits the conversion of cortisone, which is normally in-ert, to cortisol, which can cause or contribute to the symptoms of the herein described physiological and pathophysiological conditions if present in ex-cessive amounts.
The object of the present invention has surprisingly been solved in an-other aspect by providing the use of a compound of the invention as 11-13-HSD-1 inhibitor.
The terms "inhibiting, inhibition and/or retardation" are intended to refer for the purposes of the present invention to as follows: "partial or complete inhibiting, inhibition and/or retardation". In this case, it is within the specialist knowledge of the average person skilled in the art to measure and determine such inhibiting, inhibition, and/or retardation by means of the usual methods of measurement and determination. Thus, a partial inhibiting, inhibition and/or retardation, for example, can be measured and determined in relation to a complete inhibiting, inhibition and/or retardation.
The object of the present invention has surprisingly been solved in an-other aspect by providing a medicament comprising at least one compound of the invention.
The object of the present invention has surprisingly been solved in an-other aspect by providing a medicament comprising at least one compound of the invention for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, which are caused, mediated and/or propagated by high cortisol levels. A corresponding use for the preparation of
The object of the present invention has surprisingly been solved in an-other aspect by providing the use of a compound of the invention as 11-13-HSD-1 inhibitor.
The terms "inhibiting, inhibition and/or retardation" are intended to refer for the purposes of the present invention to as follows: "partial or complete inhibiting, inhibition and/or retardation". In this case, it is within the specialist knowledge of the average person skilled in the art to measure and determine such inhibiting, inhibition, and/or retardation by means of the usual methods of measurement and determination. Thus, a partial inhibiting, inhibition and/or retardation, for example, can be measured and determined in relation to a complete inhibiting, inhibition and/or retardation.
The object of the present invention has surprisingly been solved in an-other aspect by providing a medicament comprising at least one compound of the invention.
The object of the present invention has surprisingly been solved in an-other aspect by providing a medicament comprising at least one compound of the invention for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, which are caused, mediated and/or propagated by high cortisol levels. A corresponding use for the preparation of
- 41 -a medicament for the treatment and/or prophylaxis of the aforementioned conditions is intended to be comprised.
The object of the present invention has surprisingly been solved in an-other aspect by providing a medicament comprising at least one compound of the invention for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions selected from the group consisting of metabolic syndrome, diabetes, especially non-insulin dependent diabetes mellitus, prediabetes, insulin resistance, low glucose tolerance, hyperglyce-mia, obesity and weight-related disorders, lipid disorders such as dyslipide-mia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL
levels or high LDL levels, glaucoma, osteoporosis, glucocorticoid-mediated effects on neuronal function, such as cognitive impairment, anxiety or de-pression, neurodegenerative disease, immune disorders such as tuberculo-sis, leprosy or psoriasis, hypertension, atherosclerosis and its sequelae, vas-cular restenosis, cardiovascular diseases, pancreatitis, retinopathy, neuropa-thy and nephropathy. A corresponding use for the preparation of a medica-ment for the treatment and/or prophylaxis of the aforementioned conditions is intended to be comprised.
In another aspect of the invention, a method of treating a condition se-lected from the group consisting of: hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hy-pertriglyceridemia, hypercholesterolemia, low MEL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Metabolic Syndrome, hypertension and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment is disclosed, comprising administering to the patient at least one compound of the invention in an amount that is effective to treat said condi-tion.
The object of the present invention has surprisingly been solved in an-other aspect by providing a medicament comprising at least one compound of the invention for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions selected from the group consisting of metabolic syndrome, diabetes, especially non-insulin dependent diabetes mellitus, prediabetes, insulin resistance, low glucose tolerance, hyperglyce-mia, obesity and weight-related disorders, lipid disorders such as dyslipide-mia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL
levels or high LDL levels, glaucoma, osteoporosis, glucocorticoid-mediated effects on neuronal function, such as cognitive impairment, anxiety or de-pression, neurodegenerative disease, immune disorders such as tuberculo-sis, leprosy or psoriasis, hypertension, atherosclerosis and its sequelae, vas-cular restenosis, cardiovascular diseases, pancreatitis, retinopathy, neuropa-thy and nephropathy. A corresponding use for the preparation of a medica-ment for the treatment and/or prophylaxis of the aforementioned conditions is intended to be comprised.
In another aspect of the invention, a method of treating a condition se-lected from the group consisting of: hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hy-pertriglyceridemia, hypercholesterolemia, low MEL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Metabolic Syndrome, hypertension and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment is disclosed, comprising administering to the patient at least one compound of the invention in an amount that is effective to treat said condi-tion.
-42 -In another aspect of the invention, a method of delaying the onset of a condition selected from the group consisting of hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipi-demia, hypertriglyceridemia, hypercholesterolemia, low EMIL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreati-tis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Metabolic Syndrome, hypertension and other conditions and disorders where insulin resistance is a component in a mammalian patient in need of such treatment is disclosed, comprising administering to the patient at least one compound of the invention in an amount that is effective to delay the onset of said condition.
In another aspect of the invention, a method of reducing the risk of devel-oping a condition selected from the group consisting of hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pan-creatitis, abdominal obesity, neurodegenerative disease, retinopathy, neph-ropathy, neuropathy, Metabolic Syndrome, hypertension and other conditions and disorders where insulin resistance is a component in a mammalian pa-tient in need of such treatment is disclosed, comprising administering to the patient at least one compound of then invention in an amount that is effective to reduce the risk of developing said condition.
Compounds of the invention may be used in combination with one or more other active substances (ingredients, drugs) in the treatment, preven-tion, suppression or amelioration of diseases or conditions for which com-pounds of the invention or the other substances have utility. Typically the combination of the drugs is safer or more effective than either drug alone, or the combination is safer or more effective than would it be expected based on the additive properties of the individual drugs. Such other drug(s) may be administered, by a route and in an amount commonly used contennporane-
In another aspect of the invention, a method of reducing the risk of devel-oping a condition selected from the group consisting of hyperglycemia, low glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pan-creatitis, abdominal obesity, neurodegenerative disease, retinopathy, neph-ropathy, neuropathy, Metabolic Syndrome, hypertension and other conditions and disorders where insulin resistance is a component in a mammalian pa-tient in need of such treatment is disclosed, comprising administering to the patient at least one compound of then invention in an amount that is effective to reduce the risk of developing said condition.
Compounds of the invention may be used in combination with one or more other active substances (ingredients, drugs) in the treatment, preven-tion, suppression or amelioration of diseases or conditions for which com-pounds of the invention or the other substances have utility. Typically the combination of the drugs is safer or more effective than either drug alone, or the combination is safer or more effective than would it be expected based on the additive properties of the individual drugs. Such other drug(s) may be administered, by a route and in an amount commonly used contennporane-
- 43 -ously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other drugs, a combination product containing such other drug(s) and the compound of the invention is preferred. However, combination therapy also includes therapies in which the compound of the invention and one or more other drugs are ad-ministered on different overlapping schedules. It is contemplated that when used in combination with other active ingredients, the compound of the pre-sent invention or the other active ingredient or both may be used effectively in lower doses than when each is used alone. Accordingly, the pharmaceuti-cal compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the invention.
Examples of other active substances that may be administered in combi-nation with a compound of the invention, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:
dipeptidyl peptidase IV (DP-IV) inhibitors; insulin sensitizing agents including PPARy agonists such as the glitazones (e.g. troglitazone, pioglitazone, engli-tazone, MCC-555, rosiglitazone, and the like) and other PPAR ligands, in-cluding PPARa/y dual agonists, such as KRP-297, and PPARa agonists such as gemfibrozil, clofibrate, fenofibrate and bezafibrate, and biguanides, such as metformin and phenformin; insulin or insulin mimetics; sulfonylureas and other insulin secretagogues such as tolbutamide, glipizide, meglitinide and related materials; a-glucosidase inhibitors, such as acarbose; glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088 and WO 00/69810; GLP-1, GLP-1 analogs, and GLP-1 receptor agonists such as those disclosed in WO 00/42026 and WO 00/59887; GIP, GIP mimetics such as those disclosed in WO 00/58360, and GIP receptor agonists; PACAP, PACAP mimetics, and PACAP receptor 3 agonists such as those disclosed in WO 01/23420; cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, rosuvastatin, and other stating), bile-acid sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), nicotinyl alcohol,
Examples of other active substances that may be administered in combi-nation with a compound of the invention, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:
dipeptidyl peptidase IV (DP-IV) inhibitors; insulin sensitizing agents including PPARy agonists such as the glitazones (e.g. troglitazone, pioglitazone, engli-tazone, MCC-555, rosiglitazone, and the like) and other PPAR ligands, in-cluding PPARa/y dual agonists, such as KRP-297, and PPARa agonists such as gemfibrozil, clofibrate, fenofibrate and bezafibrate, and biguanides, such as metformin and phenformin; insulin or insulin mimetics; sulfonylureas and other insulin secretagogues such as tolbutamide, glipizide, meglitinide and related materials; a-glucosidase inhibitors, such as acarbose; glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088 and WO 00/69810; GLP-1, GLP-1 analogs, and GLP-1 receptor agonists such as those disclosed in WO 00/42026 and WO 00/59887; GIP, GIP mimetics such as those disclosed in WO 00/58360, and GIP receptor agonists; PACAP, PACAP mimetics, and PACAP receptor 3 agonists such as those disclosed in WO 01/23420; cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, rosuvastatin, and other stating), bile-acid sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), nicotinyl alcohol,
-44 -nicotinic acid or a salt thereof, inhibitors of cholesterol absorption, such as ezetimibe and beta-sitosterol, acyl CoA:cholesterol acyltransferase inhibitors, such as, for example, avasimibe, and anti-oxidants, such as probucol;
PPAR8 agonists, such as those disclosed in WO 97/28149; antiobesity corn-pounds such as fenfluramine, dextenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y1 or Y5 antagonists, CB 1 receptor inverse agonists and antagonists, adrenergic receptor agonists, melanocortin- receptor ago-nists, in particular melanocortin-4 receptor agonists, ghrelin antagonists, and melanin-concentrating hormone (MCH) receptor antagonists; ileal bile acid transporter inhibitors; agents intended for use in inflammatory conditions other than glucocorticoids, such as aspirin, non-steroidal anti-inflammatory drugs, azulfidine, and selective cyclooxygenase-2 inhibitors; protein tyrosine phosphatase 1B (PTP-1B) inhibitors; antihypertensives including those acting on the angiotensin or renin systems, such as angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists or renin inhibitors, such as cap-topril, cilazapril, enalapril, fosinopril, lisinopril, quinapril, ramapril, zofenopril, candesartan, cilexetil, eprosartan, irbesartan, losartan, tasosartan, telnisar-tan, and valsartan; and inhibitors of cholesteryl ester transfer protein (CETP).
The above combinations include a compound of structural formula I, or a pharmaceutically acceptable salt or solvate thereof, with one or more other active compounds. Non limiting examples include combinations of com-pounds of structural formula I with two or more active compounds selected from biguanides, sulfonylureas, HMG- CoA reductase inhibitors, PPAR ago-nists, PTP-1B inhibitors, DP-IV inhibitors, and anti-obesity compounds.
Antiobesity compounds that can be combined with compounds of the in-vention include fenfluramine, dexfenfluramine, phentermine, sibutramine, orl-istat, neuropeptide Y1 or Y5 antagonists, cannabinoid CB 1 receptor antago-nists or inverse agonists, melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists, ghrelin antagonists, and melanin-concentrating hormone (MCH) receptor antagonists. For a review of anti-obesity compounds that can be combined with compounds of structural for-mula I, see S. Chaki et al., "Recent advances in feeding suppressing agents:
PPAR8 agonists, such as those disclosed in WO 97/28149; antiobesity corn-pounds such as fenfluramine, dextenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y1 or Y5 antagonists, CB 1 receptor inverse agonists and antagonists, adrenergic receptor agonists, melanocortin- receptor ago-nists, in particular melanocortin-4 receptor agonists, ghrelin antagonists, and melanin-concentrating hormone (MCH) receptor antagonists; ileal bile acid transporter inhibitors; agents intended for use in inflammatory conditions other than glucocorticoids, such as aspirin, non-steroidal anti-inflammatory drugs, azulfidine, and selective cyclooxygenase-2 inhibitors; protein tyrosine phosphatase 1B (PTP-1B) inhibitors; antihypertensives including those acting on the angiotensin or renin systems, such as angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists or renin inhibitors, such as cap-topril, cilazapril, enalapril, fosinopril, lisinopril, quinapril, ramapril, zofenopril, candesartan, cilexetil, eprosartan, irbesartan, losartan, tasosartan, telnisar-tan, and valsartan; and inhibitors of cholesteryl ester transfer protein (CETP).
The above combinations include a compound of structural formula I, or a pharmaceutically acceptable salt or solvate thereof, with one or more other active compounds. Non limiting examples include combinations of com-pounds of structural formula I with two or more active compounds selected from biguanides, sulfonylureas, HMG- CoA reductase inhibitors, PPAR ago-nists, PTP-1B inhibitors, DP-IV inhibitors, and anti-obesity compounds.
Antiobesity compounds that can be combined with compounds of the in-vention include fenfluramine, dexfenfluramine, phentermine, sibutramine, orl-istat, neuropeptide Y1 or Y5 antagonists, cannabinoid CB 1 receptor antago-nists or inverse agonists, melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists, ghrelin antagonists, and melanin-concentrating hormone (MCH) receptor antagonists. For a review of anti-obesity compounds that can be combined with compounds of structural for-mula I, see S. Chaki et al., "Recent advances in feeding suppressing agents:
- 45 -potential therapeutic strategy for the treatment of obesity," Expert Opin.
Ther.
Patents, 11: 1677-1692 (2001) and D. Spanswick and K. Lee, "Emerging an-tiobesity drugs," Expert Opin. Emerging Drugs, 8: 217- 237 (2003).
Neuropeptide Y5 antagonists that can be combined with compounds of the inventtion include those disclosed in US 6,335,345 and WO 01/14376;
and specific compounds identified as GW59884A; GW569180A; LY366377;
and COP-71683A.
Cannabinoid CB 1 receptor antagonists that can be combined with corn-pounds of formula I include those disclosed in WO 03/007887; US 5,624,941, such as rimonabant; WO 02/076949, such as SLV-319; US 6,028,084;
WO 98/41519; WO 00/10968; WO 99/02499; US 5,532,237; and US 5,292,736.
Melanocortin receptor agonists that can be combined with compounds of the invention include those disclosed in WO 03/009847; WO 02/068388;
WO 99/64002; WO 00/74679; WO 01/70708; and WO 01/70337 as well as those disclosed in J.D. Speake et al., "Recent advances in the development of melanocortin-4 receptor agonists, Expert Opin. Ther. Patents, 12: 1631-1638 (2002).
In another aspect of the invention, a method of treating a condition se-lected from the group consisting of hyperglycemia, low glucose tolerance, in-sulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hyper-triglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Metabolic Syndrome, hypertension and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment, comprising administering to the patient an effective amount of at least one compound of the invention and at least one compound selected from the group consisting of: dipeptidyl peptidase-IV (DP-IV) ; inhibitors;
insu-lin sensitizing agents selected from the group consisting of PPARy agonists,
Ther.
Patents, 11: 1677-1692 (2001) and D. Spanswick and K. Lee, "Emerging an-tiobesity drugs," Expert Opin. Emerging Drugs, 8: 217- 237 (2003).
Neuropeptide Y5 antagonists that can be combined with compounds of the inventtion include those disclosed in US 6,335,345 and WO 01/14376;
and specific compounds identified as GW59884A; GW569180A; LY366377;
and COP-71683A.
Cannabinoid CB 1 receptor antagonists that can be combined with corn-pounds of formula I include those disclosed in WO 03/007887; US 5,624,941, such as rimonabant; WO 02/076949, such as SLV-319; US 6,028,084;
WO 98/41519; WO 00/10968; WO 99/02499; US 5,532,237; and US 5,292,736.
Melanocortin receptor agonists that can be combined with compounds of the invention include those disclosed in WO 03/009847; WO 02/068388;
WO 99/64002; WO 00/74679; WO 01/70708; and WO 01/70337 as well as those disclosed in J.D. Speake et al., "Recent advances in the development of melanocortin-4 receptor agonists, Expert Opin. Ther. Patents, 12: 1631-1638 (2002).
In another aspect of the invention, a method of treating a condition se-lected from the group consisting of hyperglycemia, low glucose tolerance, in-sulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hyper-triglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels, atherosclerosis and its sequelae, vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy, nephropathy, neuropathy, Metabolic Syndrome, hypertension and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment, comprising administering to the patient an effective amount of at least one compound of the invention and at least one compound selected from the group consisting of: dipeptidyl peptidase-IV (DP-IV) ; inhibitors;
insu-lin sensitizing agents selected from the group consisting of PPARy agonists,
- 46 -PPARa agonists, PPARary dual agonists, and biguanides; insulin and insulin mimetics; sulfonylureas and other insulin secretagogues; a-glucosidase in-hibitors; glucagon receptor antagonists; GLP-1, GLP-1 analogs, and GLP-1 receptor agonists; GIP,G1P mimetics, and GIP receptor agonists; PACAP, PACAP mimetics, and PACAP receptor 3 agonists; cholesterol lowering agents selected from the group consisting of HMG-CoA reductase inhibitors, sequestrants, nicotinyl alcohol, nicotinic acid and salts thereof, inhibitors of cholesterol absorption, acyl CoA:cholesterol acyltransferase inhibitors, and anti-oxidants; PPARS agonists; antiobesity compounds; ileal bile acid trans-porter inhibitors; anti-inflammatory agents, excluding glucocorticoids;
protein tyrosine phosphatase 1B (PTP-1B) inhibitors; and antihypertensives including those acting on the angiotensin or renin systems, such as angiotensin con-verting enzyme inhibitors, angiotensin II receptor antagonists or renin inhibi-tors, such as captopril, cilazapril, enalapril, fosinopril, lisinopril, quinapril, ramapril, zofenopril, candesartan, cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, and valsartan; said compounds being administered to the patient in an amount that is effective to treat said condition.
Dipeptidyl peptidase-IV inhibitors that can be combined with compounds of structural formula I include those disclosed in WO 03/004498, WO 03/004496;
EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/00025;
WO 03/002530; WO 03/002531; WO 03/002553; WO 03/002593;
WO 03/000180; and WO 03/000181. Specific DP-IV inhibitor compounds in-clude isoleucine thiazolidide; NVP-DPP728; P32/98; and LAF 237.
In another aspect of the invention, a method of treating a condition se-lected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidennia, hypertriglyceridemia, and dyslipidemia, in a mammalian patient in need of such treatment is disclosed, comprising administering to the patient a therapeutically effective amount of at least one compound of the invention and an HMG-CoA reductase inhibitor.
protein tyrosine phosphatase 1B (PTP-1B) inhibitors; and antihypertensives including those acting on the angiotensin or renin systems, such as angiotensin con-verting enzyme inhibitors, angiotensin II receptor antagonists or renin inhibi-tors, such as captopril, cilazapril, enalapril, fosinopril, lisinopril, quinapril, ramapril, zofenopril, candesartan, cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, and valsartan; said compounds being administered to the patient in an amount that is effective to treat said condition.
Dipeptidyl peptidase-IV inhibitors that can be combined with compounds of structural formula I include those disclosed in WO 03/004498, WO 03/004496;
EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/00025;
WO 03/002530; WO 03/002531; WO 03/002553; WO 03/002593;
WO 03/000180; and WO 03/000181. Specific DP-IV inhibitor compounds in-clude isoleucine thiazolidide; NVP-DPP728; P32/98; and LAF 237.
In another aspect of the invention, a method of treating a condition se-lected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidennia, hypertriglyceridemia, and dyslipidemia, in a mammalian patient in need of such treatment is disclosed, comprising administering to the patient a therapeutically effective amount of at least one compound of the invention and an HMG-CoA reductase inhibitor.
- 47 -More particularly, in another aspect of the invention, a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hyper-trig lyceridemia and dyslipidemia, in a mammalian patient in need of such treatment is disclosed, wherein the HMG-CoA reductase inhibitor is a statin.
Even more particularly, in another aspect of the invention, a method of treating a condition selected from the group consisting of hypercholes-terolemia, atherosclerosis, low HAL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of such treatment is disclosed, wherein the HMG-CoA reductase inhibitor is a statin selected from the group consisting of lovastatin, simvastatin, pravas-tatin, cerivastatin, fluvastatin, atorvastatin, itavastatin and rosuvastatin.
In another aspect of the invention, a method of reducing the risk of devel-oping a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hyper-triglyceridemia and dyslipidemia, and the sequelae of such conditions is dis-closed comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of at least one compound of the invention and an HMG-CoA reductase inhibitor.
In another aspect of the invention, a method for delaying the onset or re-ducing the risk of; developing atherosclerosis in a human patient in need of such treatment is disclosed comprising administering to said patient an effec-tive amount of at least one compound of the invention and an HMG-CoA re-ductase inhibitor.
More particularly, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-CoA reductase inhibitor is a statin.
Even more particularly, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treat-ment is disclosed, wherein the HMG-CoA reductase inhibitor is a statin se-
Even more particularly, in another aspect of the invention, a method of treating a condition selected from the group consisting of hypercholes-terolemia, atherosclerosis, low HAL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of such treatment is disclosed, wherein the HMG-CoA reductase inhibitor is a statin selected from the group consisting of lovastatin, simvastatin, pravas-tatin, cerivastatin, fluvastatin, atorvastatin, itavastatin and rosuvastatin.
In another aspect of the invention, a method of reducing the risk of devel-oping a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hyper-triglyceridemia and dyslipidemia, and the sequelae of such conditions is dis-closed comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of at least one compound of the invention and an HMG-CoA reductase inhibitor.
In another aspect of the invention, a method for delaying the onset or re-ducing the risk of; developing atherosclerosis in a human patient in need of such treatment is disclosed comprising administering to said patient an effec-tive amount of at least one compound of the invention and an HMG-CoA re-ductase inhibitor.
More particularly, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-CoA reductase inhibitor is a statin.
Even more particularly, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treat-ment is disclosed, wherein the HMG-CoA reductase inhibitor is a statin se-
-48-.
lected from the group consisting of: lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, and rosuvastatin.
Even more particularly, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treat-ment is disclosed, wherein the statin is simvastatin.
In another aspect of the invention, a method for delaying the onset or re-ducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-CoA reductase inhibitor is a statin and further comprising administering a cholesterol absorption inhibitor.
More particularly, in another aspect of the invention, a method for delay-ing the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-CoA reduc-tase inhibitor is a statin and the cholesterol absorption inhibitor is ezetimibe.
In another aspect of the invention, a medicament according to above as-pects and embodiments is provided, wherein in such medicament comprises at least one additional pharmacologically active substance (drug, ingredient).
In a preferred embodiment the at least one pharmacologically active sub-stance is a substance as described herein.
In another aspect of the invention, a medicament according to above as-pects and embodiments is provided, wherein the medicament is applied be-fore and/or during and/or after treatment with at least one additional pharma-cologically active substance.
In a preferred embodiment the at least one pharmacologically active sub-stance is a substance as described herein.
In another aspect of the invention, a pharmaceutical composition compris-ing a therapeutically effective amount of at least one compound of the inven-tion is provided.
lected from the group consisting of: lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, and rosuvastatin.
Even more particularly, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treat-ment is disclosed, wherein the statin is simvastatin.
In another aspect of the invention, a method for delaying the onset or re-ducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-CoA reductase inhibitor is a statin and further comprising administering a cholesterol absorption inhibitor.
More particularly, in another aspect of the invention, a method for delay-ing the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-CoA reduc-tase inhibitor is a statin and the cholesterol absorption inhibitor is ezetimibe.
In another aspect of the invention, a medicament according to above as-pects and embodiments is provided, wherein in such medicament comprises at least one additional pharmacologically active substance (drug, ingredient).
In a preferred embodiment the at least one pharmacologically active sub-stance is a substance as described herein.
In another aspect of the invention, a medicament according to above as-pects and embodiments is provided, wherein the medicament is applied be-fore and/or during and/or after treatment with at least one additional pharma-cologically active substance.
In a preferred embodiment the at least one pharmacologically active sub-stance is a substance as described herein.
In another aspect of the invention, a pharmaceutical composition compris-ing a therapeutically effective amount of at least one compound of the inven-tion is provided.
- 49 -In a preferred embodiment, the pharmaceutical composition contains at least one additional compound selected from the group consisting of physio-logically acceptable excipients, auxiliaries, adjuvants, diluents, carriers and/or additional pharmaceutically active substance other than the compounds of the invention.
In another aspect of the invention, a pharmaceutical composition is dis-closed which comprises at least one compound of the invention, a compound selected from the group consisting of: DP-IV inhibitors; insulin I sensitizing agents selected from the group consisting of PPARa agonists; PPARy ago-nists, PPARa/y dual agonists, and biguanides; insulin and insulin mimetics;
sulfonylureas and other insulin secretagogues; oc-glucosidase inhibitors; glu-cagon receptor antagonists; GLP-1, GLP-1 analogs, and GLP-1 receptor agonists; GIP, GIP mimetics, and GIP receptor agonists; PACAP, PACAP
mimetics, and PACAP receptor 3 agonists; cholesterol lowering agents se-lected from the group consisting of HMG-CoA reductase inhibitors, segues-tants, (nicotinyl alcohol, nicotinic acid or a salt thereof, inhibitors of choles-terol absorption, acyl CoA:cholesterol acyltransferase inhibitors, and anti-oxidants; PPAR8 agonists; antiobesity compounds; Heal bile acid transporter inhibitors; anti-inflammatory agents other than glucocorticoids; protein tyro-sine phosphatase 1B (PTP-1B) inhibitors; and antihypertensives including those acting on the angiotensin or renin systems, such as angiotensin con-verting enzyme inhibitors, angiotensin II receptor antagonists or renin inhibi-tors, such as captopril, cilazapril, enalapril, fosinopril, lisinopril, quinapril, ramapril, zofenopril, candesartan, cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, and valsartan; inhibitors of cholesteryl ester transfer protein (CETP); and a pharmaceutically acceptable carrier.
A further embodiment of the present invention is a process for the manu-facture of said pharmaceutical compositions, characterized in that one or more compounds according to the invention and one or more compounds se-lected from the group consisting of solid, liquid or semiliquid excipients, auxil-
In another aspect of the invention, a pharmaceutical composition is dis-closed which comprises at least one compound of the invention, a compound selected from the group consisting of: DP-IV inhibitors; insulin I sensitizing agents selected from the group consisting of PPARa agonists; PPARy ago-nists, PPARa/y dual agonists, and biguanides; insulin and insulin mimetics;
sulfonylureas and other insulin secretagogues; oc-glucosidase inhibitors; glu-cagon receptor antagonists; GLP-1, GLP-1 analogs, and GLP-1 receptor agonists; GIP, GIP mimetics, and GIP receptor agonists; PACAP, PACAP
mimetics, and PACAP receptor 3 agonists; cholesterol lowering agents se-lected from the group consisting of HMG-CoA reductase inhibitors, segues-tants, (nicotinyl alcohol, nicotinic acid or a salt thereof, inhibitors of choles-terol absorption, acyl CoA:cholesterol acyltransferase inhibitors, and anti-oxidants; PPAR8 agonists; antiobesity compounds; Heal bile acid transporter inhibitors; anti-inflammatory agents other than glucocorticoids; protein tyro-sine phosphatase 1B (PTP-1B) inhibitors; and antihypertensives including those acting on the angiotensin or renin systems, such as angiotensin con-verting enzyme inhibitors, angiotensin II receptor antagonists or renin inhibi-tors, such as captopril, cilazapril, enalapril, fosinopril, lisinopril, quinapril, ramapril, zofenopril, candesartan, cilexetil, eprosartan, irbesartan, losartan, tasosartan, telmisartan, and valsartan; inhibitors of cholesteryl ester transfer protein (CETP); and a pharmaceutically acceptable carrier.
A further embodiment of the present invention is a process for the manu-facture of said pharmaceutical compositions, characterized in that one or more compounds according to the invention and one or more compounds se-lected from the group consisting of solid, liquid or semiliquid excipients, auxil-
- 50 -iaries, adjuvants, diluents, carriers and pharmaceutically active agents other than the compounds according to the invention, are converted in a suitable dosage form.
In another aspect of the invention, a kit is provided comprising a thera-peutically effective amount of at least one compound of the invention and/or at least one pharmaceutical composition as described herein and a therapeu-tically effective amount of at least one further pharmacologically active sub-stance other than the compounds of the invention.
The pharmaceutical compositions of the present invention may be admin-istered by any means that achieve their intended purpose. For example, ad-ministration may be by oral, parenteral, topical, enteral, intravenous, intra-muscular, inhalant, nasal, intraarticular, intraspinal, transtracheal, transocu-lar, subcutaneous, intraperitoneal, transdermal, or buccal routes. Alterna-tively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the re-cipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. Parenteral administration is preferred. Oral ad-ministration is especially preferred.
Suitable dosage forms include, but are not limited to capsules, tablets, pellets, dragees, semi-solids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, so-lution, syrups, aerosols, suspension, emulsion, which can be produced ac-cording to methods known in the art, for example as described below:
tablets: mixing of active ingredient/s and auxiliaries, compression of said mixture into tablets (direct compression), optionally granulation of part of mix-ture before compression.
In another aspect of the invention, a kit is provided comprising a thera-peutically effective amount of at least one compound of the invention and/or at least one pharmaceutical composition as described herein and a therapeu-tically effective amount of at least one further pharmacologically active sub-stance other than the compounds of the invention.
The pharmaceutical compositions of the present invention may be admin-istered by any means that achieve their intended purpose. For example, ad-ministration may be by oral, parenteral, topical, enteral, intravenous, intra-muscular, inhalant, nasal, intraarticular, intraspinal, transtracheal, transocu-lar, subcutaneous, intraperitoneal, transdermal, or buccal routes. Alterna-tively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the re-cipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. Parenteral administration is preferred. Oral ad-ministration is especially preferred.
Suitable dosage forms include, but are not limited to capsules, tablets, pellets, dragees, semi-solids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, so-lution, syrups, aerosols, suspension, emulsion, which can be produced ac-cording to methods known in the art, for example as described below:
tablets: mixing of active ingredient/s and auxiliaries, compression of said mixture into tablets (direct compression), optionally granulation of part of mix-ture before compression.
- 51 -capsules: mixing of active ingredient/s and auxiliaries to obtain a flowable powder, optionally granulating powder, filling powders/granulate into opened capsules, capping of capsules.
semi-solids (ointments, gels, creams): dissolving/dispersing active ingre-dient/s in an aqueous or fatty carrier; subsequent mixing of aqueous/fatty phase with complementary fatty/ aqueous phase, homogenization (creams only).
suppositories (rectal and vaginal): dissolving/dispersing active ingredi-ent/s in carrier material liquified by heat (rectal: carrier material normally a wax; vaginal: carrier normally a heated solution of a gelling agent), casting said mixture into suppository forms, annealing and withdrawal suppositories from the forms.
aerosols: dispersing/dissolving active agent/s in a propellant, bottling said mixture into an atomizer.
In general, non-chemical routes for the production of pharmaceutical compositions and/or pharmaceutical preparations comprise processing steps on suitable mechanical means known in the art that transfer one or more compounds ofthe invenion into a dosage form suitable for administration to a patient in need of such a treatment. Usually, the transfer of one or more compounds of the invention into such a dosage form comprises the addition of one or more compounds, selected from the group consisting of carriers, excipients, auxiliaries and pharmaceutical active ingredients other than the compounds of the invention. Suitable processing steps include, but are not limited to combining, milling, mixing, granulating, dissolving, dispersing, ho-mogenizing, casting and/or compressing the respective active and non-active ingredients. Mechanical means for performing said processing steps are known in the art, for example from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition. In this respect, active ingredients are preferably at least one compound of the invention and one or more additional compounds other than the compounds of the invention, which show valuable pharmaceu-
semi-solids (ointments, gels, creams): dissolving/dispersing active ingre-dient/s in an aqueous or fatty carrier; subsequent mixing of aqueous/fatty phase with complementary fatty/ aqueous phase, homogenization (creams only).
suppositories (rectal and vaginal): dissolving/dispersing active ingredi-ent/s in carrier material liquified by heat (rectal: carrier material normally a wax; vaginal: carrier normally a heated solution of a gelling agent), casting said mixture into suppository forms, annealing and withdrawal suppositories from the forms.
aerosols: dispersing/dissolving active agent/s in a propellant, bottling said mixture into an atomizer.
In general, non-chemical routes for the production of pharmaceutical compositions and/or pharmaceutical preparations comprise processing steps on suitable mechanical means known in the art that transfer one or more compounds ofthe invenion into a dosage form suitable for administration to a patient in need of such a treatment. Usually, the transfer of one or more compounds of the invention into such a dosage form comprises the addition of one or more compounds, selected from the group consisting of carriers, excipients, auxiliaries and pharmaceutical active ingredients other than the compounds of the invention. Suitable processing steps include, but are not limited to combining, milling, mixing, granulating, dissolving, dispersing, ho-mogenizing, casting and/or compressing the respective active and non-active ingredients. Mechanical means for performing said processing steps are known in the art, for example from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition. In this respect, active ingredients are preferably at least one compound of the invention and one or more additional compounds other than the compounds of the invention, which show valuable pharmaceu-
- 52 -tical properties, preferably those pharmaceutical active agents other than the compounds of the invention, which are disclosed herein.
Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal use are sup-positories, suitable for parenteral use are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical use are ointments, creams or powders. The compounds of the invention may also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations. The preparations indi-cated may be sterilised and/or comprise assistants, such as lubricants, pre-servatives, stabilisers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavours and/or a plurality of further active ingredients, for example one or more vitamins.
Suitable excipients are organic or inorganic substances, which are suit-able for enteral (for example oral), parenteral or topical administration and do not react with the compounds of the invention, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triace-tate, gelatine, carbohydrates, such as lactose, sucrose, mannitol, sorbitol or starch (maize starch, wheat starch, rice starch, potato starch), cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatine, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellu-lose, polyvinyl pyrrolidone and/or vaseline.
If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
Auxiliaries include, without limitation, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used,
Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal use are sup-positories, suitable for parenteral use are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical use are ointments, creams or powders. The compounds of the invention may also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations. The preparations indi-cated may be sterilised and/or comprise assistants, such as lubricants, pre-servatives, stabilisers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavours and/or a plurality of further active ingredients, for example one or more vitamins.
Suitable excipients are organic or inorganic substances, which are suit-able for enteral (for example oral), parenteral or topical administration and do not react with the compounds of the invention, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triace-tate, gelatine, carbohydrates, such as lactose, sucrose, mannitol, sorbitol or starch (maize starch, wheat starch, rice starch, potato starch), cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatine, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellu-lose, polyvinyl pyrrolidone and/or vaseline.
If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
Auxiliaries include, without limitation, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used,
- 53 -which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyeth-ylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices or to provide a dosage form affording the advantage of prolonged ac-tion, the tablet, dragee or pill can comprise an inner dosage and an outer dosage component me latter being in the form of an envelope over the for-mer. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and permits the inner compo-nent to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, acetyl alcohol, solutions of suitable cellulose preparations such as acetyl-cellulose phthalate, cellulose acetate or hy-droxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical applica-tion and do not react with the novel compounds, for example water, vegeta-ble oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops or suppositories are used for enteral administration, solutions, preferably oily or aqueous solu-tions, furthermore suspensions, emulsions or implants, are used for par-enteral administration, and ointments, creams or powders are used for topical application. The compounds of the invention can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injec-tion preparations.
The preparations indicated can be sterilized and/or can contain excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifi-ers, salts for affecting the osmotic pressure, buffer substances, colorants, fla-
Suitable carrier substances are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical applica-tion and do not react with the novel compounds, for example water, vegeta-ble oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops or suppositories are used for enteral administration, solutions, preferably oily or aqueous solu-tions, furthermore suspensions, emulsions or implants, are used for par-enteral administration, and ointments, creams or powders are used for topical application. The compounds of the invention can also be lyophilized and the lyophilizates obtained can be used, for example, for the production of injec-tion preparations.
The preparations indicated can be sterilized and/or can contain excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifi-ers, salts for affecting the osmotic pressure, buffer substances, colorants, fla-
- 54 -vourings and/or aromatizers. They can, if desired, also contain one or more further active compounds, e.g. one or more vitamins.
Other pharmaceutical preparations, which can be used orally include push-fit capsules made of gelatine, as well as soft, sealed capsules made of gelatine and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules, which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft cap-sules, the active compounds are preferably dissolved or suspended in suit-able liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emul-sions with edible oils such as cottonseed oil, sesame oil, coconut oil or pea-nut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dis-persing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium car-boxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatine.
Suitable formulations for parenteral administration include aqueous solu-tions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered.
Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, including, for example, sodium carboxy-methyl cellulose, sorbitol, and/or dextran, optionally, the suspension may also contain stabilizers.
Other pharmaceutical preparations, which can be used orally include push-fit capsules made of gelatine, as well as soft, sealed capsules made of gelatine and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules, which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft cap-sules, the active compounds are preferably dissolved or suspended in suit-able liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emul-sions with edible oils such as cottonseed oil, sesame oil, coconut oil or pea-nut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dis-persing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium car-boxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatine.
Suitable formulations for parenteral administration include aqueous solu-tions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered.
Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400 (the compounds are soluble in PEG-400).
Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, including, for example, sodium carboxy-methyl cellulose, sorbitol, and/or dextran, optionally, the suspension may also contain stabilizers.
- 55 -For administration as an inhalation spray, it is possible to use sprays in which the active ingredient is either dissolved or suspended in a propellant gas or propellant gas mixture (for example CO2 or chlorofluorocarbons). The active ingredient is advantageously used here in micronized form, in which case one or more additional physiologically acceptable solvents may be pre-sent, for example ethanol. Inhalation solutions can be administered with the aid of conventional inhalers.
Possible pharmaceutical preparations, which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
In addition, it is also possible to use gelatine rectal capsules, which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hy-drocarbons.
For use in medicine, the compounds of the present invention will be in the form of pharmaceutically acceptable salts. Other salts may, however, be use-ful in the preparation of the compounds of the invention or of their pharma-ceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for exam-ple be formed by mixing a solution of the compound according to the inven-tion with a solution of a pharmaceutically acceptable acid such as hydrochlo-ric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alka-line earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic bases, e.g. quaternary ammonium salts.
Possible pharmaceutical preparations, which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons.
In addition, it is also possible to use gelatine rectal capsules, which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hy-drocarbons.
For use in medicine, the compounds of the present invention will be in the form of pharmaceutically acceptable salts. Other salts may, however, be use-ful in the preparation of the compounds of the invention or of their pharma-ceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for exam-ple be formed by mixing a solution of the compound according to the inven-tion with a solution of a pharmaceutically acceptable acid such as hydrochlo-ric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alka-line earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic bases, e.g. quaternary ammonium salts.
- 56 -The pharmaceutical preparations can be employed as medicaments in human and veterinary medicine. As used herein, the term "effective amount"
means that amount of a drug or pharmaceutical agent that will elicit the bio-logical or medical response of a tissue, system, animal or human that is be-ing sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in im-proved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or dis-order. The term also includes within its scope amounts effective to enhance normal physiological function. Said therapeutic effective amount of one or more of the compounds of the invention is known to the skilled artisan or can be easily determined by standard methods known in the art.
The compounds of the invention and the additional active substances are generally administered analogously to commercial preparations. Usually, suitable doses that are therapeutically effective lie in the range between 0.0005 mg and 1000 mg, preferably between 0.005 mg and 500 mg and es-pecially between 0.5 mg and 100 mg per dose unit. The daily dose is pref-erably between about 0.001 mg/kg and 10 mg/kg of body weight.
Those of skill will readily appreciate that dose levels can vary as a func-tion of the specific compound, the severity of the symptoms and the suscep-tibility of the subject to side effects. Some of the specific compounds are more potent than others. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.
For the purpose of the present invention, all mammalian species are re-garded as being comprised. In a preferred embodiment, such mammals are selected from the group consisting of "primate, human, rodent, equine, bo-vine, canine, feline, domestic animals, cattle, livestock, pets, cow, sheep, pig, goat, horse, pony, donkey, hinny, mule, hare, rabbit, cat, dog, guinea pig,
means that amount of a drug or pharmaceutical agent that will elicit the bio-logical or medical response of a tissue, system, animal or human that is be-ing sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in im-proved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or dis-order. The term also includes within its scope amounts effective to enhance normal physiological function. Said therapeutic effective amount of one or more of the compounds of the invention is known to the skilled artisan or can be easily determined by standard methods known in the art.
The compounds of the invention and the additional active substances are generally administered analogously to commercial preparations. Usually, suitable doses that are therapeutically effective lie in the range between 0.0005 mg and 1000 mg, preferably between 0.005 mg and 500 mg and es-pecially between 0.5 mg and 100 mg per dose unit. The daily dose is pref-erably between about 0.001 mg/kg and 10 mg/kg of body weight.
Those of skill will readily appreciate that dose levels can vary as a func-tion of the specific compound, the severity of the symptoms and the suscep-tibility of the subject to side effects. Some of the specific compounds are more potent than others. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.
For the purpose of the present invention, all mammalian species are re-garded as being comprised. In a preferred embodiment, such mammals are selected from the group consisting of "primate, human, rodent, equine, bo-vine, canine, feline, domestic animals, cattle, livestock, pets, cow, sheep, pig, goat, horse, pony, donkey, hinny, mule, hare, rabbit, cat, dog, guinea pig,
- 57 -hamster, rat, mouse". More preferably, such mammals are humans. Animal models are of interest for experimental investigations, providing a model for treatment of human diseases.
The specific dose for the individual patient depends, however, on the mul-titude of factors, for example on the efficacy of the specific compounds em-ployed, on the age, body weight, general state of health, the sex, the kind of diet, on the time and route of administration, on the excretion rate, the kind of administration and the dosage form to be administered, the pharmaceutical combination and severity of the particular disorder to which the therapy re-lates. The specific therapeutic effective dose for the individual patient can readily be determined by routine experimentation, for example by the doctor or physician, which advises or attends the therapeutic treatment.
In the case of many disorders, the susceptibility of a particular cell to treatment with the subject compounds may be determined by in vitro testing.
Typically a culture of the cell is combined with a subject compound at varying concentrations for a period of time sufficient to allow the active agents to show a relevant reaction, usually between about one hour and one week. For in vitro testing, cultured cells from a biopsy sample may be used.
Even without further details, it is assumed that a person skilled in the art will be able to utilise the above description in the broadest scope. The pre-ferred embodiments should therefore merely be regarded as descriptive dis-closure, which is absolutely not limiting in any way.
Above and below, all temperatures are indicated in C. In the following examples, "conventional work-up" means that, if necessary, the solvent is removed, water is added if necessary, the pH is adjusted, if necessary, to be-tween 2 and 10, depending on the constitution of the end product, the mix-ture is extracted with ethyl acetate or dichloromethane, the phases are sepa-rated, the organic phase is washed with saturated NaHCO3 solution, if de-sired with water and saturated NaCI solution, is dried over sodium sulfate, fil-tered and evaporated, and the product is purified by chromatography on sil-
The specific dose for the individual patient depends, however, on the mul-titude of factors, for example on the efficacy of the specific compounds em-ployed, on the age, body weight, general state of health, the sex, the kind of diet, on the time and route of administration, on the excretion rate, the kind of administration and the dosage form to be administered, the pharmaceutical combination and severity of the particular disorder to which the therapy re-lates. The specific therapeutic effective dose for the individual patient can readily be determined by routine experimentation, for example by the doctor or physician, which advises or attends the therapeutic treatment.
In the case of many disorders, the susceptibility of a particular cell to treatment with the subject compounds may be determined by in vitro testing.
Typically a culture of the cell is combined with a subject compound at varying concentrations for a period of time sufficient to allow the active agents to show a relevant reaction, usually between about one hour and one week. For in vitro testing, cultured cells from a biopsy sample may be used.
Even without further details, it is assumed that a person skilled in the art will be able to utilise the above description in the broadest scope. The pre-ferred embodiments should therefore merely be regarded as descriptive dis-closure, which is absolutely not limiting in any way.
Above and below, all temperatures are indicated in C. In the following examples, "conventional work-up" means that, if necessary, the solvent is removed, water is added if necessary, the pH is adjusted, if necessary, to be-tween 2 and 10, depending on the constitution of the end product, the mix-ture is extracted with ethyl acetate or dichloromethane, the phases are sepa-rated, the organic phase is washed with saturated NaHCO3 solution, if de-sired with water and saturated NaCI solution, is dried over sodium sulfate, fil-tered and evaporated, and the product is purified by chromatography on sil-
- 58 -ica gel, by preparative HPLC and/or by crystallisation. The purified com-pounds are, If desired, freeze-dried.
Mass spectrometry (MS): ESI (electrospray ionisation) (WH).
List of Abbreviations and Acronyms:
AcOH acetic acid, anh anhydrous, atm atmosphere(s), BOG tert-butoxycarbonyl CDI 1X-carbonyl diimiclazole, conc concentrated, d day(s), dec decomposition, DMAC NN-dimethylacetamide, DMPU 1 ,3-dimethy1-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, DMF NN-dimethylformamide, DMSO
dirnethylsulfoxide, DPPA diphenylphosphoryl azide, EDCI 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide, Et0Ac ethyl acetate, Et0H etha-nol (100%), Et20 diethyl ether, Et3N triethylamine, h hour(s), Me0H metha-nol, pet. ether petroleum ether (boiling range 30-60 C), temp. temperature, THF tetrahydrofuran, TFA trifluoroAcOH, Tf trifluoromethanesulfonyl.
The invention is explained in more detail by means of the following examples without, however, being restricted thereto.
=
Mass spectrometry (MS): ESI (electrospray ionisation) (WH).
List of Abbreviations and Acronyms:
AcOH acetic acid, anh anhydrous, atm atmosphere(s), BOG tert-butoxycarbonyl CDI 1X-carbonyl diimiclazole, conc concentrated, d day(s), dec decomposition, DMAC NN-dimethylacetamide, DMPU 1 ,3-dimethy1-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, DMF NN-dimethylformamide, DMSO
dirnethylsulfoxide, DPPA diphenylphosphoryl azide, EDCI 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide, Et0Ac ethyl acetate, Et0H etha-nol (100%), Et20 diethyl ether, Et3N triethylamine, h hour(s), Me0H metha-nol, pet. ether petroleum ether (boiling range 30-60 C), temp. temperature, THF tetrahydrofuran, TFA trifluoroAcOH, Tf trifluoromethanesulfonyl.
The invention is explained in more detail by means of the following examples without, however, being restricted thereto.
=
- 59 -Examples Example 1 ¨ General Method To 5.5 g (15.4 mmol) of 4-Thiocarbamoyl-piperidine-1-carboxylic acid tort-butyl ester in 50 ml of ethyl acetate was added 3.4 g (40.9 mmol, 2eq) of so-dium acetate and 3.7 ml (26.6 mmol, 1.3 eq) of ethyl bromopyruvate at 5 C.
The reaction was allowed to pursue for 16 hrs. After addition of water, the compound was extracted 3X CH2Cl2. The organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo. The compound was re-cristallized in diisopropyl oxyde to give 5.53 g (15.43 mmol, 75%) of a white solid.
To 54.2 g (0.15 mol) of the above compound was added 300 ml of acetic acid and the reaction was heated to 100 C for 1h30. The mixture was con-centrated, CH2Cl2 was the added and the organic layer washed with a solu-tion of NaHCO3, dried over Na2SO4 and concentrated in vacuo to give 45.7 g (0.13 mol, 89%) of the desired cyclized compound which was saponified by addition of Ethanol (300 ml) and 16.1 ml (1.16 mot, 1.2 eq) of a sodium hy-droxyde solution (10N) for 16 h at room temperature. After concentration in vacuo and addition of water (300 ml), washing with CH2Cl2, the solution was then acidified with AcOH. The compound which precipitates is filtered and washed with water to give 34.63 g ( 0.11 mol, 83%) of a white solid.
To 1.960 g (6.2 mmol) of the free carboxylic acid under N2 was added 20 ml DMF, and 0.974 g (6.2 mmol, 1 eq) of decahydroquinolin-4ol, 2.838 ml (21.9 mmol, 3.5 eq) of diisopropylamine and 2.4 g (6.2 mmol, 1 eq) of HBTU.
The mixture was stirred at room temperature for 16hrs and the reaction quenched with water (100 ml) and the compound extracted with AcOEt (3X) and washed with a solution of NaHCO3, citrique acid 15%, water, NaCI satu-rated solution, and finally dried over Na2SO4 and concentrated to give 2.42 g (5.3 mmol, 86%) of an oil.
The reaction was allowed to pursue for 16 hrs. After addition of water, the compound was extracted 3X CH2Cl2. The organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo. The compound was re-cristallized in diisopropyl oxyde to give 5.53 g (15.43 mmol, 75%) of a white solid.
To 54.2 g (0.15 mol) of the above compound was added 300 ml of acetic acid and the reaction was heated to 100 C for 1h30. The mixture was con-centrated, CH2Cl2 was the added and the organic layer washed with a solu-tion of NaHCO3, dried over Na2SO4 and concentrated in vacuo to give 45.7 g (0.13 mol, 89%) of the desired cyclized compound which was saponified by addition of Ethanol (300 ml) and 16.1 ml (1.16 mot, 1.2 eq) of a sodium hy-droxyde solution (10N) for 16 h at room temperature. After concentration in vacuo and addition of water (300 ml), washing with CH2Cl2, the solution was then acidified with AcOH. The compound which precipitates is filtered and washed with water to give 34.63 g ( 0.11 mol, 83%) of a white solid.
To 1.960 g (6.2 mmol) of the free carboxylic acid under N2 was added 20 ml DMF, and 0.974 g (6.2 mmol, 1 eq) of decahydroquinolin-4ol, 2.838 ml (21.9 mmol, 3.5 eq) of diisopropylamine and 2.4 g (6.2 mmol, 1 eq) of HBTU.
The mixture was stirred at room temperature for 16hrs and the reaction quenched with water (100 ml) and the compound extracted with AcOEt (3X) and washed with a solution of NaHCO3, citrique acid 15%, water, NaCI satu-rated solution, and finally dried over Na2SO4 and concentrated to give 2.42 g (5.3 mmol, 86%) of an oil.
- 60 -To 2.35 g (5.2 mmol) of the starting material in 20 ml CH2Cl2 was added at 5 C was added 13 ml of a HCl/dioxanne solution (4M/L). The reaction was allowed to warm up at room temperature and stirred for 16hrs. After concen-tration in vacuo, water was added, the compound washed with CH2Cl2, NaOH solution (10 N) was then added, and the compound was finally ex-tracted with CH2Cl2, washed with a saturated solution of NaCI, dried over Na2SO4 and concentrated to give an oil (1.30 g, 3.7 mmol, 71 %).
The following compounds were made in a similar way as described above (table 1).
Table 1 Example Name LC/MS
2-Piperidin-4-yl-thiazole-4-Retention time (Rt)= 1.3 1.1 carboxylic acid cyclohexyl- M+1=334,1 cyclopropyl-amide (Octahydro-quinolin-1-yI)-(2- Rt= 1.33 1.2 piperidin-4-yl-thiazol-4-y1)- M+1=334,1 methanone
The following compounds were made in a similar way as described above (table 1).
Table 1 Example Name LC/MS
2-Piperidin-4-yl-thiazole-4-Retention time (Rt)= 1.3 1.1 carboxylic acid cyclohexyl- M+1=334,1 cyclopropyl-amide (Octahydro-quinolin-1-yI)-(2- Rt= 1.33 1.2 piperidin-4-yl-thiazol-4-y1)- M+1=334,1 methanone
- 61 -Example 2¨ Method A
To 200 mg (0.5 mmol) of (Octahydro-quinolin-1-y1)-(2-piperidin-4-yl-thiazol-4-y1)-methanone in 2 ml acetonitrile was added 94.9 mg (0.6 mmol, 1.2 eq) of potassium carbonate and 62.6 p1(0.5 mmol, 1 eq) of 4-fluoro-5 benzoyl chloride. The mixture was stirred at room temperature for 20 hrs and the reaction quenched with the addition of water. The compound was ex-tracted with AcOEt and then purified by flash chromatography to obtain 79 mg (0.1 mmol, 29%) of an oil.
10 The following compounds were made in a similar way as described above (table 2).
Table 2 Example Name MS
3,3-Dimethy1-1-{4-[4-2 1 (octahydro-quinoline-1- Rt=2,62 .
carbonyl)-thiazol-2-yl]- M+1=432,2 piperidin-1-yll-butan-1-one (Octahydro-quinolin-1-yI)-{2-[1-(pyridine-3-carbonyl)-2.2M+1=439,2 piperidin-4-ylPhiazol-4-y1}-methanone 2-(1-Cyclohexanecarbonyl-piperidin-4-y1)-thiazole-4-2.3 M+1=440 carboxylic acid cyclohexyl-cyclopropyl-amide 2-(1-Cyclopentanecarbonyl-piperidin-4-y1)-thiazole-4-2.4 M+1=430,2 carboxylic acid cyclohexyl-cyclopropyl-amide M+1=416 7,82(s,2H) 4,40(m,1H) 2-(1-Cyclobutanecarbonyl-3,75(m,2H)3,32(m,5H) 2.5 piperidin-4-yI)-thiazole-4- 3,07(m,21-1) 2,67(m,2H) 2,05 carboxylic acid cyclohexyl- (m,6H) 1,73 (m,6H) 1,57 cyclopropyl-amide (m,2H) 1,23 (m,2H) 0,53 (m,211) 0,37 (m,2H) 2-(1-Cyclopropanecarbonyl- M+1=402,2 2.6 piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-
To 200 mg (0.5 mmol) of (Octahydro-quinolin-1-y1)-(2-piperidin-4-yl-thiazol-4-y1)-methanone in 2 ml acetonitrile was added 94.9 mg (0.6 mmol, 1.2 eq) of potassium carbonate and 62.6 p1(0.5 mmol, 1 eq) of 4-fluoro-5 benzoyl chloride. The mixture was stirred at room temperature for 20 hrs and the reaction quenched with the addition of water. The compound was ex-tracted with AcOEt and then purified by flash chromatography to obtain 79 mg (0.1 mmol, 29%) of an oil.
10 The following compounds were made in a similar way as described above (table 2).
Table 2 Example Name MS
3,3-Dimethy1-1-{4-[4-2 1 (octahydro-quinoline-1- Rt=2,62 .
carbonyl)-thiazol-2-yl]- M+1=432,2 piperidin-1-yll-butan-1-one (Octahydro-quinolin-1-yI)-{2-[1-(pyridine-3-carbonyl)-2.2M+1=439,2 piperidin-4-ylPhiazol-4-y1}-methanone 2-(1-Cyclohexanecarbonyl-piperidin-4-y1)-thiazole-4-2.3 M+1=440 carboxylic acid cyclohexyl-cyclopropyl-amide 2-(1-Cyclopentanecarbonyl-piperidin-4-y1)-thiazole-4-2.4 M+1=430,2 carboxylic acid cyclohexyl-cyclopropyl-amide M+1=416 7,82(s,2H) 4,40(m,1H) 2-(1-Cyclobutanecarbonyl-3,75(m,2H)3,32(m,5H) 2.5 piperidin-4-yI)-thiazole-4- 3,07(m,21-1) 2,67(m,2H) 2,05 carboxylic acid cyclohexyl- (m,6H) 1,73 (m,6H) 1,57 cyclopropyl-amide (m,2H) 1,23 (m,2H) 0,53 (m,211) 0,37 (m,2H) 2-(1-Cyclopropanecarbonyl- M+1=402,2 2.6 piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-
-62 -cyclopropyl-amide 2-[1-(3-Cyclopentyl-propiony0-piperidin-4-A-M+1=458 2.7 thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 2-[1-(2-Ethyl-butyryI)-piperidin-4-yl]-thiazole-4- M+1=432,2 .
carboxylic acid cyclohexyl-cyclopropyl-amide 2-[1-(3,3-Dimethyl-butyryI)-2.9 M+1=432,2 carboxylic acid cyclohexyl-cyclopropyl-amide 2-[1-(3-Methyl-butyryI)-2 10 piperidin-4-y1j-thiazole-4- M+1=418 .
carboxylic acid cyclohexyl-_,_ cyclopropyl-amide 2-(1-lsobutyryl-piperidin-4-2 11 yI)-thiazole-4-carboxylic M+1=404 .
acid cyclohexyl-cyclopropyl-amide 2-(1-Pentanoyl-piperidin-4-2 yI)-thiazole-4-carboxylic M+1=418 .
acid cyclohexyl-cyclopropyl-amide 2-(1-Propionyl-piperidin-4-2 13 y1)-thiazole-4-carboxylic M+1=390 .
acid cyclohexyl-cyclopropyl-amide 2-(1-Acetyl-piperidin-4-yI)-2 14 thiazole-4-carboxylic acid M+1=376 .
cyclohexyl-cyclopropyl-amide 2-[l -(Pyridine-3-carbonyl)-2 15 piperidin-4-yll-thiazole-4- M+1+439 .
carboxylic acid cyclohexyl-cyclopropyl-amide 2-[1-(4-Trifluoromethoxy-benzoy1)-piperidin-4-y1]-M+1=522 2.16 thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide [2-(1-Cyclohexanecarbonyl-2 17 piperidin-4-y1)-thiazol-4-y1]- M+1=444,2 .
(octahydro-quinolin-l-yI)-methanone [2-(1-Cyclopentanecarbonyl-M+1=430,2 2.18 piperidin-4-y1)-thiazol-4-y1]-(octahydro-quinolin-1-yI)-methanone
carboxylic acid cyclohexyl-cyclopropyl-amide 2-[1-(3,3-Dimethyl-butyryI)-2.9 M+1=432,2 carboxylic acid cyclohexyl-cyclopropyl-amide 2-[1-(3-Methyl-butyryI)-2 10 piperidin-4-y1j-thiazole-4- M+1=418 .
carboxylic acid cyclohexyl-_,_ cyclopropyl-amide 2-(1-lsobutyryl-piperidin-4-2 11 yI)-thiazole-4-carboxylic M+1=404 .
acid cyclohexyl-cyclopropyl-amide 2-(1-Pentanoyl-piperidin-4-2 yI)-thiazole-4-carboxylic M+1=418 .
acid cyclohexyl-cyclopropyl-amide 2-(1-Propionyl-piperidin-4-2 13 y1)-thiazole-4-carboxylic M+1=390 .
acid cyclohexyl-cyclopropyl-amide 2-(1-Acetyl-piperidin-4-yI)-2 14 thiazole-4-carboxylic acid M+1=376 .
cyclohexyl-cyclopropyl-amide 2-[l -(Pyridine-3-carbonyl)-2 15 piperidin-4-yll-thiazole-4- M+1+439 .
carboxylic acid cyclohexyl-cyclopropyl-amide 2-[1-(4-Trifluoromethoxy-benzoy1)-piperidin-4-y1]-M+1=522 2.16 thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide [2-(1-Cyclohexanecarbonyl-2 17 piperidin-4-y1)-thiazol-4-y1]- M+1=444,2 .
(octahydro-quinolin-l-yI)-methanone [2-(1-Cyclopentanecarbonyl-M+1=430,2 2.18 piperidin-4-y1)-thiazol-4-y1]-(octahydro-quinolin-1-yI)-methanone
- 63 -[2-(1-Cyclobutanecarbonyl-2.19 piperidin-4-y1)-thiazol-4-y1]- M+1=416 (octahydro-quinolin-1-yI)-methanone [2-(1-Cyclopropanecarbonyl-M+1+402 2.20 piperidin-4-y1)-thiazol-4-y1]-(octahydro-quinolin-1-yI)-methanone 3-Cyclopenty1-1-{4-[4-2.21 (octahydro-quinoline-1- M+1=458 carbony1)-thiazol-2-y1}-pi_peridin-1 -y1}-propan-1-one 2-Ethy1-1-{444-(octahydro-2.22 quinoline-1-carbonyl)- M+1=432,2 thiazol-2-y1]-piperidin-1-y1}-butan-1-one 3-Methy1-1-{4-[4-(octahydro-2.23 quinoline-1-carbonyI)- M+1=418 thiazol-2-yl]-piperidin-1-y1}-butan-1-one 2-Methy1-1-{444-(octahydro-quinoline-1-carbony1)- M+1=404 2.24 thiazol-2-ylypiperidin-1-y1}-propan-1-one 1-{4-[4-(Octahydro-2.25 quinoline-1-carbony1)- M+1=418 thiazol-2-yl]-piperidin-1-y1}-pentan-1-one 1-{4-[4-(Octahydro-quinoline-1-carbony1)- M+1=390 2.26 thiazol-2-y1]-piperidin-1-y1}-propan-1-one 1-{444-(Octahydro-2.27 quinoline-1-carbonyl)- M+1=376 thiazol-2-y11-piperidin-1-y1}-ethanone (Octahydro-quinolin-1-0-2.28 (241-(4-trifluoromethoxy- M+1=522 benzoy1)-piperidin-4-y1F
thiazot-4-y1}-methanone {2-[1-(4-Fluoro-benzoy1)-2.29 piperidin-4-y1]-thiazol-4-y1}- M+1=456,2 (octahydro-quinolin-1-y1)-methanone {2-[1-(4-Fluoro-benzoy1)-2.30 piperidin-411]-thiazol-4-y1}- M+1=472,1 (4-hydroxy-octahydro-quinolin-1-y1)-methanone 1-{4-[4-(4-Hydroxy-M+1=498 2.31 octahydro-quinoline-1-carbony1)-thiazol-2-y11-
thiazot-4-y1}-methanone {2-[1-(4-Fluoro-benzoy1)-2.29 piperidin-4-y1]-thiazol-4-y1}- M+1=456,2 (octahydro-quinolin-1-y1)-methanone {2-[1-(4-Fluoro-benzoy1)-2.30 piperidin-411]-thiazol-4-y1}- M+1=472,1 (4-hydroxy-octahydro-quinolin-1-y1)-methanone 1-{4-[4-(4-Hydroxy-M+1=498 2.31 octahydro-quinoline-1-carbony1)-thiazol-2-y11-
- 64 -piperidin-1-y1}-2-(4-methoxy-phenyI)-ethanone 4-[4-(4-Hydroxy-octahydro-quinoline-1-carbony1)-M+1=450,2 2.32 thiazol-2-y1]-piperidine-1-carboxylic acid tert-butyl ester 241-(2-Phenyl-butyry1)-2.33 piperidin-4-y1]-thiazole-4- M+1=480,2 carboxylic acid cyclohexyl-cyclopropyl-amide 2-{1-[2-(4-Methoxy-pheny1)-acety1]-piperidin-4-y1}-M+1=482,1 2.34 thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 2-[1-(2-Phenoxy-acetyI)-2.35 piperidin-4-yI]-thiazole-4- M+1=468 carboxylic acid cyclohexyl-cyclopropyl-amide 4-[4-(Cyclohexyl-cyclopropyl-carbamoyI)-M+1=434,1 2.36 thiazol-2-A-piperidine-1-carboxylic acid tert-butyl ester 1-{444-(Octahydro-2.37 quinoline-1-carbony1)- M+1=480 thiazol-2-y1]-piperidin-1-y1}-2-phenyl-butan-1-one 2-(4-Methoxy-phenyI)-1-{4-2.38 [4-(octahydro-quinoline-1- M+1=483 carbonyl)-thiazol-2-yl]-piperidin-1-yll-ethanone _ 1-{4-(4-(Octahydro-2.37 quinoline-1-carbony1)- M+1=468 thiazol-2-y1J-piperidin-1-y1}-2-phenoxy-ethanone 444-(Octahydro-quinoline-2.38 1-carbonylythiazol-2-01-piperidine-1-carboxylic acid tert-butyl ester 2-Pheny1-1-{4-(4-2.39 (piperidine-1-carbonyI)- M+1=426 thiazol-2-y1j-piperidin-l-y1}-butan-1-one 2-(4-Methoxy-pheny1)-1-{4-2.40 [4-(piperidine-1-carbonyl)- M+1=428 thiazol-2-y1]-piperidin-1-y1}-ethanone _ 2-Phenoxy-1-{444-M+1=414 2.41 (piperidine-1-carbony1)-thiazol-2-y9-piperidin-1-y1}-
- 65 -ethanone 4-[4-(Piperidine-l-carbonyl)-2 42 thiazol-2-yl]-piperidine-1- M+1=380,3 .
carboxylic acid tert-butyl ester 241 -(2-Phenyl-butyryI)-2 43 piperidin-4-yIJ-thiazole-4- M+1=454,1 .
carboxylic acid cyclohexyl-methyl-amide 2-{142-(4-Methoxy-phenyl)-2 44 acetyll-piperidin-4-y1}- M+1=456 .
thiazole-4-carboxylic acid cyclohexyl-methyl-amide 2-[1-(2-Phenoxy-acetyl)-piperidin-4-yI]-thiazole-4- M+1=442,1 2.45 carboxylic acid cyclohexyl-methyl-amide
carboxylic acid tert-butyl ester 241 -(2-Phenyl-butyryI)-2 43 piperidin-4-yIJ-thiazole-4- M+1=454,1 .
carboxylic acid cyclohexyl-methyl-amide 2-{142-(4-Methoxy-phenyl)-2 44 acetyll-piperidin-4-y1}- M+1=456 .
thiazole-4-carboxylic acid cyclohexyl-methyl-amide 2-[1-(2-Phenoxy-acetyl)-piperidin-4-yI]-thiazole-4- M+1=442,1 2.45 carboxylic acid cyclohexyl-methyl-amide
-66 -Example 3¨ Method B
To 200 mg (0.5 mmol) of (Octahydro-quinolin-l-y1)-(2-piperidin-4-yl-thiazol-4-y1)-methanone in 2 ml DMF was added 101.1 p1(0.5 mmol, 1 eq) of 1-Butyl-4-isocyanato-benzene. The mixture was stirred at 55 C for 16 hrs 5 and the reaction quenched with the addition of water. The compound was ex-tracted with AcOEt and then purified by flash chromatography to obtain 38 mg (0.07 mmol, 13%) of an oil.
The following compounds were made in a similar way as described above 10 (table 3).
Table 3 Example Name MS
444-(Octahydro-quinoline-1-3 carbonyl)-thiazol-2-yn- M+1=433 .1 piperidine-1-carboxylic acid sec-butylamide M+1=433 4-[4-(Octahydro-quinoline-1-7,92 (m ,1H) 5,83 (s,1H) 4,02 carbonyl)-thiazol-2-y11-3.2 (m 2H) 3,84 (m,1H) 3,21 piperidine-1-carboxylic acid (m 2H) 2,78(m,4H) 2,02-tert-butylamide 1,32 (m,16H) 1,27(s,9H) _ 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-y1]- M+1=419 3.3 piperidine-1-carboxylic acid propylamide 4-[4-(Octahydro-quinoline-1-3 4 carbonyl)-thiazol-2-y11- M+1=405 .
piperidine-1-carboxylic acid ethylamide 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-A- M+1=445 3.5 piperidine-1-carboxylic acid cyclopentylamide 4-[4-(Octahydro-quinoline-1-3 6 carbonyl)-2-y1]- M+1=419 .
piperidine-1-carboxylic acid isopropylamide 4-14-(Octahydro-quinoline-1- M+1=447 3.7 carbony1)-thiazol-2-y1]-piperidine-1-carboxylic acid
To 200 mg (0.5 mmol) of (Octahydro-quinolin-l-y1)-(2-piperidin-4-yl-thiazol-4-y1)-methanone in 2 ml DMF was added 101.1 p1(0.5 mmol, 1 eq) of 1-Butyl-4-isocyanato-benzene. The mixture was stirred at 55 C for 16 hrs 5 and the reaction quenched with the addition of water. The compound was ex-tracted with AcOEt and then purified by flash chromatography to obtain 38 mg (0.07 mmol, 13%) of an oil.
The following compounds were made in a similar way as described above 10 (table 3).
Table 3 Example Name MS
444-(Octahydro-quinoline-1-3 carbonyl)-thiazol-2-yn- M+1=433 .1 piperidine-1-carboxylic acid sec-butylamide M+1=433 4-[4-(Octahydro-quinoline-1-7,92 (m ,1H) 5,83 (s,1H) 4,02 carbonyl)-thiazol-2-y11-3.2 (m 2H) 3,84 (m,1H) 3,21 piperidine-1-carboxylic acid (m 2H) 2,78(m,4H) 2,02-tert-butylamide 1,32 (m,16H) 1,27(s,9H) _ 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-y1]- M+1=419 3.3 piperidine-1-carboxylic acid propylamide 4-[4-(Octahydro-quinoline-1-3 4 carbonyl)-thiazol-2-y11- M+1=405 .
piperidine-1-carboxylic acid ethylamide 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-A- M+1=445 3.5 piperidine-1-carboxylic acid cyclopentylamide 4-[4-(Octahydro-quinoline-1-3 6 carbonyl)-2-y1]- M+1=419 .
piperidine-1-carboxylic acid isopropylamide 4-14-(Octahydro-quinoline-1- M+1=447 3.7 carbony1)-thiazol-2-y1]-piperidine-1-carboxylic acid
- 67 -pentylamide 4-[4-(Cyclohexyl-cyclopropyl-3 8 carbamoy1)-thiazol-2-y9- M+1=433 .
piperidine-1-carboxylic acid sec-butylamide 4-[4-(Cyclohexyl-cyclopropyl-3 9 carbamoy1)-thiazol-2-y1]- M+1=433 .
piperidine-1-carboxylic acid tert-butylamide 4-[4-(Cyclohexyl-cyclopropyl-3 10 carbamoy1)-thiazol-2-y1]- M+1=419 .
piperidine-1-carboxylic acid propylamide 4-[4-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-01- M+1=405 3.11 piperidine-1-carboxylic acid ethylamide 4-[4-(Cyclohexyl-cyclopropyl-3 12 carbamoy1)-thiazol-2-y1]- M+1=445 .
piperidine-1-carboxylic acid cyclopentylamide 4-[4-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-yl]- M+1=419 3.13 piperidine-1-carboxylic acid isopropyiamide 4-[4-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-y1]- M+1=447 3.14 piperidine-1-carboxylic acid pentylamide 4-(4-(4-Hydroxy-octahydro-quinoline-1-carbony1)-thiazol- M+1=513,2 3.15 2-yI]-piperidine-1-carboxylic acid 4-methoxy-benzylamide 4-[4-(4-Hydroxy-octahydro-quinoline-1-carbony1)-thiazol- M+1=525,2 3.16 2-yI)-piperidine-1-carboxylic acid (4-butyl-phenyl)-amide 3-({4-[4-(Cyclohexyl-cyclopropyl-carbamoyI)- M+1=449,1 3.17 thiazol-2-y1Fpiperidine-1-carbony1)-amino)-propionic acid 444-(Cyclohexyl-cyclopropyl-3 18 carbamoy1)-thiazol-2-y1]- M+1=509 .
piperidine-1-carboxylic acid (4-butyl-phenyl)-amide 4-[4-(Cyclohexyl-cyclopropyl-3 19 carbamoy1)-thiazol-2-y1]- M+1=497,1 .
piperidine-1-carboxylic acid 4-methoxy-benzylamide 3 20 3-({444-[4- M+1=449,1 .
quinoline-1-carbonyI)-thiazol-
piperidine-1-carboxylic acid sec-butylamide 4-[4-(Cyclohexyl-cyclopropyl-3 9 carbamoy1)-thiazol-2-y1]- M+1=433 .
piperidine-1-carboxylic acid tert-butylamide 4-[4-(Cyclohexyl-cyclopropyl-3 10 carbamoy1)-thiazol-2-y1]- M+1=419 .
piperidine-1-carboxylic acid propylamide 4-[4-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-01- M+1=405 3.11 piperidine-1-carboxylic acid ethylamide 4-[4-(Cyclohexyl-cyclopropyl-3 12 carbamoy1)-thiazol-2-y1]- M+1=445 .
piperidine-1-carboxylic acid cyclopentylamide 4-[4-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-yl]- M+1=419 3.13 piperidine-1-carboxylic acid isopropyiamide 4-[4-(Cyclohexyl-cyclopropyl-carbamoy1)-thiazol-2-y1]- M+1=447 3.14 piperidine-1-carboxylic acid pentylamide 4-(4-(4-Hydroxy-octahydro-quinoline-1-carbony1)-thiazol- M+1=513,2 3.15 2-yI]-piperidine-1-carboxylic acid 4-methoxy-benzylamide 4-[4-(4-Hydroxy-octahydro-quinoline-1-carbony1)-thiazol- M+1=525,2 3.16 2-yI)-piperidine-1-carboxylic acid (4-butyl-phenyl)-amide 3-({4-[4-(Cyclohexyl-cyclopropyl-carbamoyI)- M+1=449,1 3.17 thiazol-2-y1Fpiperidine-1-carbony1)-amino)-propionic acid 444-(Cyclohexyl-cyclopropyl-3 18 carbamoy1)-thiazol-2-y1]- M+1=509 .
piperidine-1-carboxylic acid (4-butyl-phenyl)-amide 4-[4-(Cyclohexyl-cyclopropyl-3 19 carbamoy1)-thiazol-2-y1]- M+1=497,1 .
piperidine-1-carboxylic acid 4-methoxy-benzylamide 3 20 3-({444-[4- M+1=449,1 .
quinoline-1-carbonyI)-thiazol-
- 68 -2-y1]-piperidine-1-carbonyl}-amino)-propionic acid 4-[4-(Octahydro-quinoline-1-3 21 carbonyl)-thiazol-2-yl]- M+1=509 .
piperidine-1-carboxylic acid (4-butyl-phenyl)-amide 4-[4-(Octahydro-quinoline-1-3 22 carbonyl)-thiazol-2-y1J- M+1=497,1 .
piperidine-1-carboxylic acid 4-mettioxy-benzylarnide 3-({4-[4-(Piperidine-1-3 23 carbony1)-thiazol-2-y1J- M+1=395 .
piperidine-1-carbonyl}-amino)-propionic acid 4-[4-(Piperidine-1-carbonyI)-3 24 thiazol-2-yl]-piperidine-1- M+1=455,1 .
carboxylic acid (4-butyl-phenyl)-amide 4-[4-(Piperidine-1-carbonyI
3 25 )-thiazol-2-01-piperidine-1- M+1=443 .
carboxylic acid 4-methoxy-benzylamide 3-({4-[4-(Cyclohexyl-methyl-carbamoy1)-thiazol-2-y1]- M+1=423 3.26 piperidine-1-carbonyly amino)-propionic acid 4-[4-(Cyclohexyl-methyl-3 27 carbamoy1)-thiazol-2-y1]- M+1=483 .
piperidine-1-carboxylic acid (4-butyl-phenyl)-amide 4-[4-(Cyclohexyl-methyl-3 28 carbamoy1)-thiazol-2-yll- M+1=471,1 .
piperidine-1-carboxylic acid 4-methoxy-benzylamide
piperidine-1-carboxylic acid (4-butyl-phenyl)-amide 4-[4-(Octahydro-quinoline-1-3 22 carbonyl)-thiazol-2-y1J- M+1=497,1 .
piperidine-1-carboxylic acid 4-mettioxy-benzylarnide 3-({4-[4-(Piperidine-1-3 23 carbony1)-thiazol-2-y1J- M+1=395 .
piperidine-1-carbonyl}-amino)-propionic acid 4-[4-(Piperidine-1-carbonyI)-3 24 thiazol-2-yl]-piperidine-1- M+1=455,1 .
carboxylic acid (4-butyl-phenyl)-amide 4-[4-(Piperidine-1-carbonyI
3 25 )-thiazol-2-01-piperidine-1- M+1=443 .
carboxylic acid 4-methoxy-benzylamide 3-({4-[4-(Cyclohexyl-methyl-carbamoy1)-thiazol-2-y1]- M+1=423 3.26 piperidine-1-carbonyly amino)-propionic acid 4-[4-(Cyclohexyl-methyl-3 27 carbamoy1)-thiazol-2-y1]- M+1=483 .
piperidine-1-carboxylic acid (4-butyl-phenyl)-amide 4-[4-(Cyclohexyl-methyl-3 28 carbamoy1)-thiazol-2-yll- M+1=471,1 .
piperidine-1-carboxylic acid 4-methoxy-benzylamide
-69 -Example 4¨ Method C
To 200 mg (0.5 mmol) of (Octahydro-quinolin-1-y1)-(2-piperidin-4-yl-thiazol-4-y1)-methanone in 2 ml acetonitrile was added 94.9 mg (0.6 mmol, 1.2 eq) of potassium carbonate and 44.3 p1(0.5 mmol, 1 eq) of methanesul-5 fonyl chloride. The mixture was stirred at room temperature for 20 hrs and the reaction quenched with the addition of water. The compound was ex-tracted with AcOEt and then purified by flash chromatography to obtain 69 mg (0.1 mmol, 28%) of an oil.
10 The following compounds were made in a similar way as described above (table 4), Table 4 Example Name MS
(Octahydro-quinolin-1-yI)-[2-4 (1-trifluoromethanesulfonyl- M+1=466 .1 piperidin-4-y1)-thiazol-4-0]-methanone (2-0-(Butane-1-sulfony1)-4.2 piperidin-4-M-thiazol-4-y1}- M+1=454,1 (octahydro-quinolin-1-yI)-methanone (Octahydro-quinolin-1-yI)-{2-4 3 [1-(propane-1-sulfonyI)-M+1=440 .
piperidin-4-yll-thiazol-4-y1}-methanone [2-(1-Ethanesulfonyl-4 4 piperidin-4-y1)-thiazol-4-y11- M+1=426 .
(octahydro-quinolin-1-yI)-methanone 2-(1-Trifluoromethanesulfonyl-M+1=466 4.5 piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 2-(1-(Butane-1-sulfony1)-4 6 piperidin-4-y13-thiazole-4- M+1=454,1 .
carboxylic acid cyclohexyl-cyclopropyl-amide 4.7 2-11-(Propane-2-sulfony1)- M+1=454,1
To 200 mg (0.5 mmol) of (Octahydro-quinolin-1-y1)-(2-piperidin-4-yl-thiazol-4-y1)-methanone in 2 ml acetonitrile was added 94.9 mg (0.6 mmol, 1.2 eq) of potassium carbonate and 44.3 p1(0.5 mmol, 1 eq) of methanesul-5 fonyl chloride. The mixture was stirred at room temperature for 20 hrs and the reaction quenched with the addition of water. The compound was ex-tracted with AcOEt and then purified by flash chromatography to obtain 69 mg (0.1 mmol, 28%) of an oil.
10 The following compounds were made in a similar way as described above (table 4), Table 4 Example Name MS
(Octahydro-quinolin-1-yI)-[2-4 (1-trifluoromethanesulfonyl- M+1=466 .1 piperidin-4-y1)-thiazol-4-0]-methanone (2-0-(Butane-1-sulfony1)-4.2 piperidin-4-M-thiazol-4-y1}- M+1=454,1 (octahydro-quinolin-1-yI)-methanone (Octahydro-quinolin-1-yI)-{2-4 3 [1-(propane-1-sulfonyI)-M+1=440 .
piperidin-4-yll-thiazol-4-y1}-methanone [2-(1-Ethanesulfonyl-4 4 piperidin-4-y1)-thiazol-4-y11- M+1=426 .
(octahydro-quinolin-1-yI)-methanone 2-(1-Trifluoromethanesulfonyl-M+1=466 4.5 piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 2-(1-(Butane-1-sulfony1)-4 6 piperidin-4-y13-thiazole-4- M+1=454,1 .
carboxylic acid cyclohexyl-cyclopropyl-amide 4.7 2-11-(Propane-2-sulfony1)- M+1=454,1
- 70 -piperidin-4-y1]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 2-[1-(Propane-1-sulfony1)-4 8 piperidin-4-y1]-thiazole-4- M+1=440 .
carboxylic acid cyclohexyl-cyclopropyl-amide 2-(1-Ethanesulfonyl-4 9 piperidin-4-y1)-thiazole-4- M+1=426 .
carboxylic acid cyclohexyl-cyclopropyl-amide (Octahydro-quinolin-1-yI)-{2-4 10 (1-(thiophene-2-su(fony1)- M+1=480 .
piperidin-4-A-thiazol-4-y1}-methanone 2-[1-(Thiophene-2-sulfonyI)-4 piperidin-4-y1]-thiazole-4- M+1=480 .11 carboxylic acid cyclohexyl-cyclopropyl-amide 241-(4-Trifluoromethoxy-benzenesulfony1)-piperidin-4-M+1=558 4.12 yll-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 2-[1-(4-Fluoro-benzenesulfonyI)-piperidin-4-M+1=492 4.13 yll-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide (Octahydro-quinolin-l-yI)-{2-[1-(4-trifluoromethoxy- M+1=558 4.14 benzenesulfony1)-piperidin-4-yl]-thiazol-4-y1}-methanone {2-[1-(4-Fluoro-benzenesulfony1)-piperidin-4- M+1=492 4.15 y1]-thiazol-4-y1)-(octahydro-quinolin-l-yI)-methanone (241-(4-Fluoro-benzenesulfony1)-piperidin-4- M+1=508,1 4.16 y1]-thiazol-4-y1)-(4-hydroxy-octahydro-quinolin-1 -yI)-methanone (4-Hydroxy-octahydro-4 17 quinolin-1-y1)-[2-(1- M+1=428,1 .
methanesulfonyl-piperidin-4-y1)-thiazol-4-0]-methanone 2-[1-(2-Pyridin-4-yl-ethanesulfonyI)-piperidin-4-M+1=503 4.18 ylj-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 4.19 Piperidin-1-yl-{241-(2- M+1=449
carboxylic acid cyclohexyl-cyclopropyl-amide 2-(1-Ethanesulfonyl-4 9 piperidin-4-y1)-thiazole-4- M+1=426 .
carboxylic acid cyclohexyl-cyclopropyl-amide (Octahydro-quinolin-1-yI)-{2-4 10 (1-(thiophene-2-su(fony1)- M+1=480 .
piperidin-4-A-thiazol-4-y1}-methanone 2-[1-(Thiophene-2-sulfonyI)-4 piperidin-4-y1]-thiazole-4- M+1=480 .11 carboxylic acid cyclohexyl-cyclopropyl-amide 241-(4-Trifluoromethoxy-benzenesulfony1)-piperidin-4-M+1=558 4.12 yll-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 2-[1-(4-Fluoro-benzenesulfonyI)-piperidin-4-M+1=492 4.13 yll-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide (Octahydro-quinolin-l-yI)-{2-[1-(4-trifluoromethoxy- M+1=558 4.14 benzenesulfony1)-piperidin-4-yl]-thiazol-4-y1}-methanone {2-[1-(4-Fluoro-benzenesulfony1)-piperidin-4- M+1=492 4.15 y1]-thiazol-4-y1)-(octahydro-quinolin-l-yI)-methanone (241-(4-Fluoro-benzenesulfony1)-piperidin-4- M+1=508,1 4.16 y1]-thiazol-4-y1)-(4-hydroxy-octahydro-quinolin-1 -yI)-methanone (4-Hydroxy-octahydro-4 17 quinolin-1-y1)-[2-(1- M+1=428,1 .
methanesulfonyl-piperidin-4-y1)-thiazol-4-0]-methanone 2-[1-(2-Pyridin-4-yl-ethanesulfonyI)-piperidin-4-M+1=503 4.18 ylj-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 4.19 Piperidin-1-yl-{241-(2- M+1=449
- 71 -pyridin-4-yl-ethanesulfony1)-piperidin-4-y1]-thiazol-4-y1}-methanone 2-[1-(4-Methoxy-benzenesulfony1)-piperidin-4-M+1=504 4.20 yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 2-[1-(4-tert-Butyl-benzenesulfonyl)-piperidin-4-M+1=530,2 4.21 y1]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 2-(1-Methanesulfonyl-piperidin-4-yI)-thiazole-4- M+1=412,1 4.22 carboxylic acid cyclohexyl-cyclopropyl-amide {2-0 -(4-Methoxy-4 23 benzenesulfony1)-piperidin-4-M+1=504 .
yli-thiazol-4-y1Hoctahydro-quinolin-1-yly-methanone (2-0-(4-tert-Butyl-benzenesulfonyI)-piperidin-4- M+1=530,2 4.24 yll-thiazo1-4-y1)-(octahydro-quinolin-1-y1)-methanone _ [2-(1-Methanesulfonyl-piperidin-4-y1)-thiazol-4-y1]- M+1=412,1 4.26 (octahydro-quinolin-1-y1)-methanone M+1=450 {2-[1-(4-Methoxy-7,83 (s,1H) 7,61 (d,2H) 7,11 benzenesulfonyI)-piperidin-4- (d,2H) 3,53 (m,6H) 3,27 4.26 (s,3H) 2,99(m,1H) methanone 2,38(m,2H) 2,01 (m,2H) 1,53 (m,8H) {2-0 -(4-tert-Butyl-benzenesulfony1)-piperidin-4- M+1=476 4.27 yll-thiazo1-4-y1}-piperidin-1-yl-methanone [2-(1-Methanesulfonyl- M+1=358,1 4.28 piperidin-4-y1)-thiazol-4-y1]-piperidin-1-yl-methanone 2-[1-(4-Methoxy-benzenesulfony1)-piperidin-4- M+1=478,1 4.29 yll-thiazole-4-carboxylic acid cyclohexyl-methyl-amide M+1=504 2-[1-(4-tert-Butyl- 8,02 (s,1H) 7,62 (m,4H) benzenesulfonyI)-piperidin-4- 2,03(m,2H) 3,02(m ,3H) 4.30 ylphiazole-4-carboxylic acid 2,43(s, 3H) 2,37(m,1H) cyclohexyl-methyl-amide 2,03(m,2H) 1,76(m,2H) 1,60(m,6H) 1,25(s,9H)
yli-thiazol-4-y1Hoctahydro-quinolin-1-yly-methanone (2-0-(4-tert-Butyl-benzenesulfonyI)-piperidin-4- M+1=530,2 4.24 yll-thiazo1-4-y1)-(octahydro-quinolin-1-y1)-methanone _ [2-(1-Methanesulfonyl-piperidin-4-y1)-thiazol-4-y1]- M+1=412,1 4.26 (octahydro-quinolin-1-y1)-methanone M+1=450 {2-[1-(4-Methoxy-7,83 (s,1H) 7,61 (d,2H) 7,11 benzenesulfonyI)-piperidin-4- (d,2H) 3,53 (m,6H) 3,27 4.26 (s,3H) 2,99(m,1H) methanone 2,38(m,2H) 2,01 (m,2H) 1,53 (m,8H) {2-0 -(4-tert-Butyl-benzenesulfony1)-piperidin-4- M+1=476 4.27 yll-thiazo1-4-y1}-piperidin-1-yl-methanone [2-(1-Methanesulfonyl- M+1=358,1 4.28 piperidin-4-y1)-thiazol-4-y1]-piperidin-1-yl-methanone 2-[1-(4-Methoxy-benzenesulfony1)-piperidin-4- M+1=478,1 4.29 yll-thiazole-4-carboxylic acid cyclohexyl-methyl-amide M+1=504 2-[1-(4-tert-Butyl- 8,02 (s,1H) 7,62 (m,4H) benzenesulfonyI)-piperidin-4- 2,03(m,2H) 3,02(m ,3H) 4.30 ylphiazole-4-carboxylic acid 2,43(s, 3H) 2,37(m,1H) cyclohexyl-methyl-amide 2,03(m,2H) 1,76(m,2H) 1,60(m,6H) 1,25(s,9H)
- 72 -1,08(m,2H) 0,84 (m,2H) 2-(1-Methanesulfonyl-piperidin-4-yI)-thiazole-4- M+1=386 4.31 carboxylic acid cyclohexyl-methyl-amide
- 73 -Example 5¨ Method D
To 200 mg (0.6 mmol) of (Octahydro-quinolin-1-y1)-(2-piperidin-4-yl-thiazol-4-y1)-methanone in 3 ml DMF was added 165.7 mg (1.2 mmol, 2 eq) 5 of potassium carbonate, 10 mg (0.06 mmol, 0.1 eq) of sodium iodide and 77.28 pl of 1-bromobutane. The mixture was stirred at 100 C for 20 hrs and the reaction quenched with the addition of water. The compound was ex-tracted with AcOEt and then purified by flash chromatography to obtain 202 mg (0.5 mmol, 86%) of an oil.
The following compounds were made in a similar way as described above (table 5).
Table 5 Example Name MS
2-(1-Cyclohexylmethyl-5 piperidin-4-y1)-thiazole-4- M+1=430,2 .1 carboxylic acid cyclohexyl-cyclopropyl-amide [2-(1-Cyclohexylrnethyl-5 2 piperidin-4-y1)-thiazol-4-A- M+1=430,2 .
(octahydro-quinolin-1-yI)-methanone 2-[1-(2-Cyclohexyl-ethyl)-piperidin-4-y1J-thiazole-4- M+1=444,2 5.3 carboxylic acid cyclohexyl-cyclopropyl-amide 2-[1-(Tetrahydro-pyran-2-ylmethyl)-piperidin-4-y1F M+1=432,2 5.4 thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 2-(1-Cyanomethyl-piperidin-4-y1)-thiazole-4-carboxylic M+1=373,1 5.5 acid cyclohexyl-cyclopropyl-amide 2-(1-Carbamoylmethyl-M+1=391,1 5.6 piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-
To 200 mg (0.6 mmol) of (Octahydro-quinolin-1-y1)-(2-piperidin-4-yl-thiazol-4-y1)-methanone in 3 ml DMF was added 165.7 mg (1.2 mmol, 2 eq) 5 of potassium carbonate, 10 mg (0.06 mmol, 0.1 eq) of sodium iodide and 77.28 pl of 1-bromobutane. The mixture was stirred at 100 C for 20 hrs and the reaction quenched with the addition of water. The compound was ex-tracted with AcOEt and then purified by flash chromatography to obtain 202 mg (0.5 mmol, 86%) of an oil.
The following compounds were made in a similar way as described above (table 5).
Table 5 Example Name MS
2-(1-Cyclohexylmethyl-5 piperidin-4-y1)-thiazole-4- M+1=430,2 .1 carboxylic acid cyclohexyl-cyclopropyl-amide [2-(1-Cyclohexylrnethyl-5 2 piperidin-4-y1)-thiazol-4-A- M+1=430,2 .
(octahydro-quinolin-1-yI)-methanone 2-[1-(2-Cyclohexyl-ethyl)-piperidin-4-y1J-thiazole-4- M+1=444,2 5.3 carboxylic acid cyclohexyl-cyclopropyl-amide 2-[1-(Tetrahydro-pyran-2-ylmethyl)-piperidin-4-y1F M+1=432,2 5.4 thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide 2-(1-Cyanomethyl-piperidin-4-y1)-thiazole-4-carboxylic M+1=373,1 5.5 acid cyclohexyl-cyclopropyl-amide 2-(1-Carbamoylmethyl-M+1=391,1 5.6 piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-
- 74 -cyclopropyl-amide 2-(1-Pentyl-piperidin-4-yI)-thiazole-4-carboxylic acid M+1=404,1 5.7 cyclohexyl-cyclopropyl-amide 2-(1-lsobutyl-piperidin-4-y1)-thiazole-4-carboxylic acid M+1=390,2 5.8 cyclohexyl-cyclopropyl-amide 241-(3-Methyl-buty1)-59 piperidin-4-ylphiazole-4-M+1=404,1 carboxylic acid cyclohexyl-cyclopropyl-amide 2-(1-Butyl-piperidin-4-y1)-thiazole-4-carboxylic acid M+1=390,2 5.10 cyclohexyl-cyclopropyl-amide (2-[1-(2-Cyclohexyl-ethyl)-5.11 piperidin-4-y11-thiazol-4-y1}- M+1=444,2 (octahydro-quinolin-1-y1)-methanone (Octahydro-quinolin-1-yI)-{2-(1-(tetrahydro-pyran-2- M+1=432,2 5.12 ylmethyl)-piperidin-4-y11-thiazo1-4-y1}-methanone {4-[4-(Octahydro-quinoline-1- M+1=373,1 5.13 carbonyI)-thiazol-2-yl]-piperidin-1-yI}-acetonitrile 2-{4-[4-(Octahydro-quinoline- M+1=391,1 5.14 1-carbony1)-thiazol-2-y1]-piperidin-1-y1}-acetamide (Octahydro-quinolin-1-yI)-[2- M+1=404,1 5.15 (1-pentyl-piperidin-4-y1)-thiazol-4-y1Fmethanone _ [2-(1-lsobutyl-piperidin-4-y1)- M+1=390,2 5.16 thiazol-4-y1]-(octahydro-quinolin-1-y1)-methanone {2-[1-(3-Methyl-buty1)-517 piperidin-4-y1]-thiazol-4-y1}- M+1=404,1 .
(octahydro-quinolin-1-y1)-methanone [2-(1-Butyl-piperidin-4-yI)- M+1=390,2 5.18 thiazol-4-y1]-(octahydro-quinolin-1-yI)-methanone
(octahydro-quinolin-1-y1)-methanone [2-(1-Butyl-piperidin-4-yI)- M+1=390,2 5.18 thiazol-4-y1]-(octahydro-quinolin-1-yI)-methanone
- 75 -Example 6¨ Inhibition of 11f3-HSD-1 enzyme assay Human recombinant 11-beta-hydroxysteroid dehydrogenase type 1 (11-n-HSD-1) enzyme was expressed in E. coll. Rat and mice liver microsome frac-tions were purchased from TEBU.
5 The 11-8-HSD-1 enzyme assay was carried out in 96 well microtiter plates in a total volume of 100 pl containing 30 mM Hepes buffer, pH 7,4 with 1 mM EDTA, substrate mixture cortisone / NADPH (200 nM / 200 pM), G-6-P
(1 mM) and inhibitors in serial dilutions. Reactions were initiated by addition of 10p1 11-8-HSD-1 (3 pg) from E. coli, either as microsome fractions from rat 10 and mice liver (2,5 pg). Following mixing, the plates were shaken for minutes at 37 C. The reactions were terminated with 10 pl Acid-18beta gly-cyrrhetinic stop solution. Determinations of cortisol levels in 11-8-HSD-1 preparations were monitored by HTRF (HTRF cortisol assay from Cis bio in-ternational).
15 Activity is expressed in % of control or concentration to inhibit 50% of the enzyme activity (IC50) (table 6).
Table 6 Inhibition of Inhibition of human 11-13-Hso-1 mouse 11-f3-HSD-1 Compound IC50 (pM or nM) or IC50 (pM or nM) or AI of control at 1 pM % of control at 1 pM
1.1 1,20 pM 0,290 pM
1.2 27%
2.1 92 nM 51%
2.7 420 nM 630 nM
2.17 200 nM 340 nM
2.18 130 nM 490 nM
3.1 270 nM 470 nM
3.7 340 nM 59 nM
3.22 53 nM 500 nM
5 The 11-8-HSD-1 enzyme assay was carried out in 96 well microtiter plates in a total volume of 100 pl containing 30 mM Hepes buffer, pH 7,4 with 1 mM EDTA, substrate mixture cortisone / NADPH (200 nM / 200 pM), G-6-P
(1 mM) and inhibitors in serial dilutions. Reactions were initiated by addition of 10p1 11-8-HSD-1 (3 pg) from E. coli, either as microsome fractions from rat 10 and mice liver (2,5 pg). Following mixing, the plates were shaken for minutes at 37 C. The reactions were terminated with 10 pl Acid-18beta gly-cyrrhetinic stop solution. Determinations of cortisol levels in 11-8-HSD-1 preparations were monitored by HTRF (HTRF cortisol assay from Cis bio in-ternational).
15 Activity is expressed in % of control or concentration to inhibit 50% of the enzyme activity (IC50) (table 6).
Table 6 Inhibition of Inhibition of human 11-13-Hso-1 mouse 11-f3-HSD-1 Compound IC50 (pM or nM) or IC50 (pM or nM) or AI of control at 1 pM % of control at 1 pM
1.1 1,20 pM 0,290 pM
1.2 27%
2.1 92 nM 51%
2.7 420 nM 630 nM
2.17 200 nM 340 nM
2.18 130 nM 490 nM
3.1 270 nM 470 nM
3.7 340 nM 59 nM
3.22 53 nM 500 nM
-76 -4.1 32 nM 330 nM
_ 4.2 93 nM 210 nM
4.11 720 nM -4.18 1 pM 49%
-4.20 280 nM 1 pM
_ 4.2 93 nM 210 nM
4.11 720 nM -4.18 1 pM 49%
-4.20 280 nM 1 pM
Claims (6)
1. A thiaziole derivative which is:
a) 3,3-Dimethyl-1-{4-[4-(octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-butan-1-one;
b) (Octahydro-quinolin-1-yl)-{2-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-thiazol-4-yl}-methanone;
c) 2-(1-Cyclohexanecarbonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
d) 2-(1-Cyclopentanecarbonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
e) 2-(1-Cyclobutanecarbonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
f) 2-(1-Cyclopropanecarbonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
g) 2-[1-(3-Cyclopentyl-propionyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
h) 2-[1-(2-Ethyl-butyryl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
i) 2-[1-(3,3-Dimethyl-butyryl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
j) 2-[1-(3-Methyl-butyryl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
k) 2-(1-lsobutyryl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
l) 2-(1-Pentanoyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
m) 2-(1-Propionyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
n) 2-(1-Acetyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
o) 2-[1-(Pyridine-3-carbonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
p) 2-[1-(4-Trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
q) [2-(1-Cyclohexanecarbonyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone;
r) [2-(1-Cyclopentanecarbonyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone;
s) [2-(1-Cyclobutanecarbonyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone;
t) [2-(1-Cyclopropanecarbonyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone;
u) 3-Cyclopentyl-1-{4-[4-(octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-propan-1-one;
v) 2-Ethyl-1-{4-[4-(octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-butan-1-one;
w) 3-Methyl-1-{4-[4-(octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-butan-1-one;
x) 2-Methyl-1-{4-[4-(octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-propan-1-one;
y) 1-{4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-pentan-1-one;
z) 1-{4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-propan-1-one;
aa) 1-{4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-ethanone;
bb) (Octahydro-quinolin-1-yl)-{2-[1-(4-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl}-methanone;
cc) {2-[1-(4-Fluoro-benzoyl)-piperidin-4-yl]-thiazol-4-yl)-(octahydro-quinolin-1-yl)-methanone;
dd) {2-[1-(4-Fluoro-benzoyl)-piperidin-4-yl]-thiazol-4-yl)-(4-hydroxy-octahydro-quinolin-1-yl)-methanone;
ee) 1-{4-[4-(4-Hydroxy-octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-(4-methoxy-phenyl)-ethanone;
ff) 4-[4-(4-Hydroxy-octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester;
gg) 2-[1-(2-Phenyl-butyryl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
hh) 2-{1-[2-(4-Methoxy-phenyl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
ii) 2-[1-(2-Phenoxy-acetyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
jj) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester;
kk) 1-{4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-phenyl-butan-1-one;
ll) 2-(4-Methoxy-phenyl)-1-{4-[4-(octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-ethanone;
mm) 1-{4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-phenoxy-ethanone;
nn) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester;
ss) 2-[1-(2-Phenyl-butyryl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-methyl-amide;
tt) 2-{1-[2-(4-Methoxy-phenyl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid cyclohexyl-methyl-amide;
uu) 2-[1-(2-Phenoxy-acetyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-methyl-amide;
vv) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid sec-butylamide;
ww) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butylamide;
xx) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid propylamide;
yy) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid ethylamide;
zz) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid cyclopentylamide;
aaa) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid isopropylamide;
bbb) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid pentylamide;
ccc) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1-carboxylic acid sec-butylamide;
ddd) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-carboxylic acid tert-butylamide;
eee) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1-carboxylic acid propylamide;
fff) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1-carboxylic acid ethylamide, ggg) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1-carboxylic acid cyclopentylamide, hhh) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1-carboxylic acid isopropylamide;
iii) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-carboxylic acid pentylamide;
jjj) 4-[4-(4-Hydroxy-octahydro-quinoline-1 -carbonyl)-thiazol-2-yl]-piperidine-carboxylic acid 4-methoxy-benzylamide;
kkk) 4-[4-(4-Hydroxy-octahydro-quinoline-1 -carbonyl)-thiazol-2-yl]-piperidine-carboxylic acid (4-butyl-phenyI)-amide;
III) 3-({4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1 -carbonyI}-amino)-propionic acid;
mmm) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1 -carboxylic acid (4-butyl-phenyI)-amide;
nnn) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1 -carboxylic acid 4-methoxy-benzylamide;
ooo) 3-({4-[4-(Octahydro-quinoline-1 -carbonyl)-thiazol-2-yl]-piperidine-1 -carbonyl}-amino)-propionic acid;
ppp) 4-[4-(Octahydro-quinoline-1 -carbonyl)-thiazol-2-yl]-piperidine-1 -carboxylic acid (4-butyl-phenyI)-amide;
qqq) 4-[4-(Octahydro-quinoline-1 -carbonyl)-thiazol-2-yl]-piperidine-1 -carboxylic acid 4-methoxy-benzylamide;
uuu) 3-({4-[4-(Cyclohexyl-methyl-carbamoyl)-thiazol-2-yl]-piperidine-1-carbonyl}-amino)-propionic acid;
vvv) 4-[4-(Cyclohexyl-methyl-carbamoyl)-thiazol-2-yl]-piperidine-1 -carboxylic acid (4-butyl-phenyl)-amide;
www) 4-[4-(Cyclohexyl-methyl-carbamoyl)-thiazol-2-yl]-piperidine-1 -carboxylic acid 4-methoxy-benzylamide;
xxx) (Octahydro-quinolin-1-yl)-[2-(1-trifluoromethanesulfonyl-piperidin-4-yl)-thiazol-4-yl]-methanone;
yyy) {2-[1-(Butane-1-sulfonyl)-piperidin-4-A-thiazol-4-yl)-(octahydro-quinolin-1-yl)-methanone, zzz) (Octahydro-quinolin-1-yl)-{2-[1-(propane-1-sulfonyl)-piperidin-4-yl)-thiazol-4-yl}-methanone;
aaaa) [2-(1-Ethanesulfonyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone;
bbbb) 2-(1-Trifluoromethanesulfonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
cccc) 2-[1-(Butane-1-sulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
dddd) 2-[1-(Propane-2-sulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
eeee) 2-[1-(Propane-1-sulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
ffff) 2-(1-Ethanesulfonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
gggg) (Octahydro-quinolin-1-yl)-{2-[1-(thiophene-2-sulfonyl)-piperidin-4-yl]-thiazol-4-yl}-methanone;
hhhh) 2-[1-(Thiophene-2-sulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
iiii) 2-[1 -(4-Trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
jjjj) 2-[1 -(4-Fluoro-benzenesulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acidcyclohexyl-cyclopropyl-amide;
kkkk) (Octahydro-quinolin-1 -yl)-{2-[1-(4-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl}-methanone;
llll) {2-[1 -(4-Fluoro-benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl}-(octahydro-quinolin-1 -yl)-methanone;
mmmm) {2-[1 -(4-Fluoro-benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl}-(4-hydroxy-octahydro-quinolin-1 -yl)-methanone;
nnnn) (4-Hydroxy-octahydro-quinolin-1 -yl)-[2-(1 -methanesulfonyl-piperidin-4-yl)-thiazol-4-yl]-methanone;
oooo) 2-[1 -(2-Pyridin-4-yl-ethanesulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
qqqq) 2-[1 -(4-Methoxy-benzenesulfonyl)-piperidin-4-ylphiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
rrrr) 2-[1 -(4-tert-Butyl-benzenesulfonyl)-piperidin-4-ylHhiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
ssss) 2-(1 -Methanesulfonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide, tttt) {2-[1 -(4-Methoxy-benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl)-(octahydro-quinolin-1 -yl)-methanone;
uuuu) {2-[1-(4-tert-Butyl-benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl}-(octahydro-quinolin-1-yl)-methanone;
vvvv) [2-(1-Methanesulfonyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone;
zzzz) 2-[1-(4-Methoxy-benzenesulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-methyl-amide;
aaaaa) 2-[1-(4-tert-Butyl-benzenesulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-methyl-amide;
bbbbb) 2-(1-Methanesulfonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-methyl-amide;
ccccc) 2-(1-Cyclohexylmethyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
ddddd) [2-(1-Cyclohexylmethyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone;
eeeee) 2-[1-(2-Cyclohexyl-ethyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
fffff) 2-[1-(Tetrahydro-pyran-2-ylmethyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
ggggg) 2-(1-Cyanomethyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
hhhhh) 2-(1-Carbamoylmethyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
iiii) 2-(1 -Pentyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
jjjj) 2-(1 -Isobutyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
kkkkk) 2-[1 -(3-Methyl-butyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
llll) 2-(1 -Butyl-piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
mmmmm) {2-[1 -(2-Cyclohexyl-ethyl)-piperidin-4-yl]-thiazol-4-yl}-(octahydro-quinolin-1 -yI)-methanone;
nnnnn) (Octahydro-quinolin-1 -yl)-{2-[1 -(tetrahydro-pyran-2-ylmethyl)-piperidin-4-yl]-thiazol-4-yl}-methanone;
oooo) {4-[4-(Octahydro-quinoline-1 -carbonyl)-thiazol-2-yl]-piperidin-1 -yl}-acetonitrile;
ppppp) 2-{4-[4-(Octahydro-quinoline-1 -carbonyl)-thiazol-2-yl]-piperidin-1 -yI}-acetamide;
qqqqq) (Octahydro-quinolin-1 -yl)-[2-(1 -pentyl-piperidin-4-yl)-thiazol-4-yl]-methanone;
rrrrr) [2-(1 -Isobutyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1 -yl)-methanone;
sssss) {2-[1 -(3-Methyl-butyl)-piperidin-4-yl]-thiazol-4-yl]-octahydro-quinolin-1 -yl)-methanone; or ttttt) [2-[1 -Butyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1 -yI)-methanone, or a physiologically-acceptable salt thereof.
a) 3,3-Dimethyl-1-{4-[4-(octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-butan-1-one;
b) (Octahydro-quinolin-1-yl)-{2-[1-(pyridine-3-carbonyl)-piperidin-4-yl]-thiazol-4-yl}-methanone;
c) 2-(1-Cyclohexanecarbonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
d) 2-(1-Cyclopentanecarbonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
e) 2-(1-Cyclobutanecarbonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
f) 2-(1-Cyclopropanecarbonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
g) 2-[1-(3-Cyclopentyl-propionyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
h) 2-[1-(2-Ethyl-butyryl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
i) 2-[1-(3,3-Dimethyl-butyryl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
j) 2-[1-(3-Methyl-butyryl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
k) 2-(1-lsobutyryl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
l) 2-(1-Pentanoyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
m) 2-(1-Propionyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
n) 2-(1-Acetyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
o) 2-[1-(Pyridine-3-carbonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
p) 2-[1-(4-Trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
q) [2-(1-Cyclohexanecarbonyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone;
r) [2-(1-Cyclopentanecarbonyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone;
s) [2-(1-Cyclobutanecarbonyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone;
t) [2-(1-Cyclopropanecarbonyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone;
u) 3-Cyclopentyl-1-{4-[4-(octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-propan-1-one;
v) 2-Ethyl-1-{4-[4-(octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-butan-1-one;
w) 3-Methyl-1-{4-[4-(octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-butan-1-one;
x) 2-Methyl-1-{4-[4-(octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-propan-1-one;
y) 1-{4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-pentan-1-one;
z) 1-{4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-propan-1-one;
aa) 1-{4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-ethanone;
bb) (Octahydro-quinolin-1-yl)-{2-[1-(4-trifluoromethoxy-benzoyl)-piperidin-4-yl]-thiazol-4-yl}-methanone;
cc) {2-[1-(4-Fluoro-benzoyl)-piperidin-4-yl]-thiazol-4-yl)-(octahydro-quinolin-1-yl)-methanone;
dd) {2-[1-(4-Fluoro-benzoyl)-piperidin-4-yl]-thiazol-4-yl)-(4-hydroxy-octahydro-quinolin-1-yl)-methanone;
ee) 1-{4-[4-(4-Hydroxy-octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-(4-methoxy-phenyl)-ethanone;
ff) 4-[4-(4-Hydroxy-octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester;
gg) 2-[1-(2-Phenyl-butyryl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
hh) 2-{1-[2-(4-Methoxy-phenyl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
ii) 2-[1-(2-Phenoxy-acetyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
jj) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester;
kk) 1-{4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-phenyl-butan-1-one;
ll) 2-(4-Methoxy-phenyl)-1-{4-[4-(octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-ethanone;
mm) 1-{4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidin-1-yl}-2-phenoxy-ethanone;
nn) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester;
ss) 2-[1-(2-Phenyl-butyryl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-methyl-amide;
tt) 2-{1-[2-(4-Methoxy-phenyl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid cyclohexyl-methyl-amide;
uu) 2-[1-(2-Phenoxy-acetyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-methyl-amide;
vv) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid sec-butylamide;
ww) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid tert-butylamide;
xx) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid propylamide;
yy) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid ethylamide;
zz) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid cyclopentylamide;
aaa) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid isopropylamide;
bbb) 4-[4-(Octahydro-quinoline-1-carbonyl)-thiazol-2-yl]-piperidine-1-carboxylic acid pentylamide;
ccc) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1-carboxylic acid sec-butylamide;
ddd) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-carboxylic acid tert-butylamide;
eee) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1-carboxylic acid propylamide;
fff) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1-carboxylic acid ethylamide, ggg) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1-carboxylic acid cyclopentylamide, hhh) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1-carboxylic acid isopropylamide;
iii) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-carboxylic acid pentylamide;
jjj) 4-[4-(4-Hydroxy-octahydro-quinoline-1 -carbonyl)-thiazol-2-yl]-piperidine-carboxylic acid 4-methoxy-benzylamide;
kkk) 4-[4-(4-Hydroxy-octahydro-quinoline-1 -carbonyl)-thiazol-2-yl]-piperidine-carboxylic acid (4-butyl-phenyI)-amide;
III) 3-({4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1 -carbonyI}-amino)-propionic acid;
mmm) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1 -carboxylic acid (4-butyl-phenyI)-amide;
nnn) 4-[4-(Cyclohexyl-cyclopropyl-carbamoyl)-thiazol-2-yl]-piperidine-1 -carboxylic acid 4-methoxy-benzylamide;
ooo) 3-({4-[4-(Octahydro-quinoline-1 -carbonyl)-thiazol-2-yl]-piperidine-1 -carbonyl}-amino)-propionic acid;
ppp) 4-[4-(Octahydro-quinoline-1 -carbonyl)-thiazol-2-yl]-piperidine-1 -carboxylic acid (4-butyl-phenyI)-amide;
qqq) 4-[4-(Octahydro-quinoline-1 -carbonyl)-thiazol-2-yl]-piperidine-1 -carboxylic acid 4-methoxy-benzylamide;
uuu) 3-({4-[4-(Cyclohexyl-methyl-carbamoyl)-thiazol-2-yl]-piperidine-1-carbonyl}-amino)-propionic acid;
vvv) 4-[4-(Cyclohexyl-methyl-carbamoyl)-thiazol-2-yl]-piperidine-1 -carboxylic acid (4-butyl-phenyl)-amide;
www) 4-[4-(Cyclohexyl-methyl-carbamoyl)-thiazol-2-yl]-piperidine-1 -carboxylic acid 4-methoxy-benzylamide;
xxx) (Octahydro-quinolin-1-yl)-[2-(1-trifluoromethanesulfonyl-piperidin-4-yl)-thiazol-4-yl]-methanone;
yyy) {2-[1-(Butane-1-sulfonyl)-piperidin-4-A-thiazol-4-yl)-(octahydro-quinolin-1-yl)-methanone, zzz) (Octahydro-quinolin-1-yl)-{2-[1-(propane-1-sulfonyl)-piperidin-4-yl)-thiazol-4-yl}-methanone;
aaaa) [2-(1-Ethanesulfonyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone;
bbbb) 2-(1-Trifluoromethanesulfonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
cccc) 2-[1-(Butane-1-sulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
dddd) 2-[1-(Propane-2-sulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
eeee) 2-[1-(Propane-1-sulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
ffff) 2-(1-Ethanesulfonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
gggg) (Octahydro-quinolin-1-yl)-{2-[1-(thiophene-2-sulfonyl)-piperidin-4-yl]-thiazol-4-yl}-methanone;
hhhh) 2-[1-(Thiophene-2-sulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
iiii) 2-[1 -(4-Trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
jjjj) 2-[1 -(4-Fluoro-benzenesulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acidcyclohexyl-cyclopropyl-amide;
kkkk) (Octahydro-quinolin-1 -yl)-{2-[1-(4-trifluoromethoxy-benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl}-methanone;
llll) {2-[1 -(4-Fluoro-benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl}-(octahydro-quinolin-1 -yl)-methanone;
mmmm) {2-[1 -(4-Fluoro-benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl}-(4-hydroxy-octahydro-quinolin-1 -yl)-methanone;
nnnn) (4-Hydroxy-octahydro-quinolin-1 -yl)-[2-(1 -methanesulfonyl-piperidin-4-yl)-thiazol-4-yl]-methanone;
oooo) 2-[1 -(2-Pyridin-4-yl-ethanesulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
qqqq) 2-[1 -(4-Methoxy-benzenesulfonyl)-piperidin-4-ylphiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
rrrr) 2-[1 -(4-tert-Butyl-benzenesulfonyl)-piperidin-4-ylHhiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
ssss) 2-(1 -Methanesulfonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide, tttt) {2-[1 -(4-Methoxy-benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl)-(octahydro-quinolin-1 -yl)-methanone;
uuuu) {2-[1-(4-tert-Butyl-benzenesulfonyl)-piperidin-4-yl]-thiazol-4-yl}-(octahydro-quinolin-1-yl)-methanone;
vvvv) [2-(1-Methanesulfonyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone;
zzzz) 2-[1-(4-Methoxy-benzenesulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-methyl-amide;
aaaaa) 2-[1-(4-tert-Butyl-benzenesulfonyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-methyl-amide;
bbbbb) 2-(1-Methanesulfonyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-methyl-amide;
ccccc) 2-(1-Cyclohexylmethyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
ddddd) [2-(1-Cyclohexylmethyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1-yl)-methanone;
eeeee) 2-[1-(2-Cyclohexyl-ethyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
fffff) 2-[1-(Tetrahydro-pyran-2-ylmethyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
ggggg) 2-(1-Cyanomethyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
hhhhh) 2-(1-Carbamoylmethyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
iiii) 2-(1 -Pentyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
jjjj) 2-(1 -Isobutyl-piperidin-4-yl)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
kkkkk) 2-[1 -(3-Methyl-butyl)-piperidin-4-yl]-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
llll) 2-(1 -Butyl-piperidin-4-yI)-thiazole-4-carboxylic acid cyclohexyl-cyclopropyl-amide;
mmmmm) {2-[1 -(2-Cyclohexyl-ethyl)-piperidin-4-yl]-thiazol-4-yl}-(octahydro-quinolin-1 -yI)-methanone;
nnnnn) (Octahydro-quinolin-1 -yl)-{2-[1 -(tetrahydro-pyran-2-ylmethyl)-piperidin-4-yl]-thiazol-4-yl}-methanone;
oooo) {4-[4-(Octahydro-quinoline-1 -carbonyl)-thiazol-2-yl]-piperidin-1 -yl}-acetonitrile;
ppppp) 2-{4-[4-(Octahydro-quinoline-1 -carbonyl)-thiazol-2-yl]-piperidin-1 -yI}-acetamide;
qqqqq) (Octahydro-quinolin-1 -yl)-[2-(1 -pentyl-piperidin-4-yl)-thiazol-4-yl]-methanone;
rrrrr) [2-(1 -Isobutyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1 -yl)-methanone;
sssss) {2-[1 -(3-Methyl-butyl)-piperidin-4-yl]-thiazol-4-yl]-octahydro-quinolin-1 -yl)-methanone; or ttttt) [2-[1 -Butyl-piperidin-4-yl)-thiazol-4-yl]-(octahydro-quinolin-1 -yI)-methanone, or a physiologically-acceptable salt thereof.
2. Medicament comprising at least one thiazole derivative as claimed in claim 1 for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, which are caused, mediated and/or propagated by high cortisol levels.
3. Medicament comprising at least one thiazole derivative as claimed in claim 1 for use in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions selected from the group consisting of metabolic syndrome, diabetes, non-insulin dependent diabetes mellitus, prediabetes, insulin resistance, low glucose tolerance, hyperglycemia, obesity and weight-related disorders, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels or high LDL levels, glaucoma, osteoporosis, glucocorticoid-mediated effects on neuronal function, cognitive impairment, anxiety or depression, neurodegenerative disease, immune disorders tuberculosis, leprosy or psoriasis, hypertension, atherosclerosis and its sequelae, vascular restenosis, cardiovascular diseases, pancreatitis, retinopathy, neuropathy and nephropathy.
4. The medicament as claimed in claim 2 to 3, wherein the medicament is adapted for administration before and/or during and/or after treatment with at least one additional pharmacologically active substance.
5. Pharmaceutical composition comprising at least one thiazole derivative as claimed in claim 1, and a pharmaceutically-acceptable carrier.
6. Pharmaceutical composition according to claim 5, wherein it contains at least one additional compound selected from the group consisting of physiologically acceptable excipients, auxiliaries, adjuvants, diluents and/or carriers.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08290424 | 2008-05-05 | ||
EP08290424.4 | 2008-05-05 | ||
PCT/EP2009/002607 WO2009135581A2 (en) | 2008-05-05 | 2009-04-08 | Novel nip thiazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2723431A1 CA2723431A1 (en) | 2009-11-12 |
CA2723431C true CA2723431C (en) | 2016-11-22 |
Family
ID=40935480
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA2723431A Active CA2723431C (en) | 2008-05-05 | 2009-04-08 | Nip thiazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 |
Country Status (18)
Country | Link |
---|---|
US (1) | US8546575B2 (en) |
EP (1) | EP2271405B1 (en) |
JP (1) | JP5735412B2 (en) |
KR (1) | KR101604366B1 (en) |
CN (1) | CN102015026B (en) |
AR (1) | AR072666A1 (en) |
AU (1) | AU2009243812B2 (en) |
BR (1) | BRPI0911497B8 (en) |
CA (1) | CA2723431C (en) |
CO (1) | CO6331305A2 (en) |
EA (2) | EA018920B1 (en) |
EC (1) | ECSP10010656A (en) |
ES (1) | ES2432383T3 (en) |
IL (1) | IL208989A (en) |
MX (1) | MX2010011917A (en) |
NZ (1) | NZ589691A (en) |
WO (1) | WO2009135581A2 (en) |
ZA (1) | ZA201008723B (en) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101140520B1 (en) * | 2007-06-01 | 2012-04-30 | 에프. 호프만-라 로슈 아게 | Piperidine-amide derivatives |
WO2011107494A1 (en) | 2010-03-03 | 2011-09-09 | Sanofi | Novel aromatic glycoside derivatives, medicaments containing said compounds, and the use thereof |
US8530413B2 (en) | 2010-06-21 | 2013-09-10 | Sanofi | Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments |
TW201215387A (en) | 2010-07-05 | 2012-04-16 | Sanofi Aventis | Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament |
TW201215388A (en) | 2010-07-05 | 2012-04-16 | Sanofi Sa | (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments |
TW201221505A (en) | 2010-07-05 | 2012-06-01 | Sanofi Sa | Aryloxyalkylene-substituted hydroxyphenylhexynoic acids, process for preparation thereof and use thereof as a medicament |
WO2013037390A1 (en) | 2011-09-12 | 2013-03-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
EP2760862B1 (en) | 2011-09-27 | 2015-10-21 | Sanofi | 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2015005305A1 (en) | 2013-07-09 | 2015-01-15 | 小野薬品工業株式会社 | Alxr agonist compound |
CN104910083A (en) * | 2015-07-13 | 2015-09-16 | 佛山市赛维斯医药科技有限公司 | Alkoxylphenyl triazole sulfoxide 11beta-HSD1 inhibitor, preparation method and application thereof |
CN104910084A (en) * | 2015-07-13 | 2015-09-16 | 佛山市赛维斯医药科技有限公司 | Terminal amido replaced triazole sulfoxide, preparation method and application thereof |
EP3235813A1 (en) | 2016-04-19 | 2017-10-25 | Cidqo 2012, S.L. | Aza-tetra-cyclo derivatives |
CN111655687A (en) * | 2017-09-08 | 2020-09-11 | Pi工业有限公司 | Novel fungicidal heterocyclic compounds |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7754709B2 (en) * | 2003-06-10 | 2010-07-13 | Solvay Pharmaceuticals Bv | Tetracyclic thiophenepyrimidinone compounds as inhibitors of 17β hydroxysteroid dehydrogenase compounds |
US20070231263A1 (en) * | 2004-04-13 | 2007-10-04 | Jun Qiu | Human G protein-coupled receptor and modulators thereof for the treatment of hyperglycemia and related disorders |
EP1637529A1 (en) * | 2004-09-20 | 2006-03-22 | 4Sc Ag | Novel piperidin-4-yl-thiazole-carboxamide analogues as inhibitors of T-cell proliferation and uses thereof |
DE102006010923A1 (en) * | 2006-03-09 | 2007-09-13 | Saltigo Gmbh | Process for the preparation of chloro-1,4-dimethoxybenzene |
CN101405278A (en) * | 2006-03-15 | 2009-04-08 | 4Sc股份公司 | Novel heterocyclic NF-kB inhibitors |
BRPI0709595A2 (en) * | 2006-03-15 | 2011-07-19 | 4Sc Ag | heterocyclic nf-kapab inhibitors |
-
2009
- 2009-04-08 ES ES09741800T patent/ES2432383T3/en active Active
- 2009-04-08 EP EP09741800.8A patent/EP2271405B1/en active Active
- 2009-04-08 CN CN200980116875.5A patent/CN102015026B/en active Active
- 2009-04-08 MX MX2010011917A patent/MX2010011917A/en active IP Right Grant
- 2009-04-08 KR KR1020107027260A patent/KR101604366B1/en active IP Right Grant
- 2009-04-08 BR BRPI0911497A patent/BRPI0911497B8/en active IP Right Grant
- 2009-04-08 WO PCT/EP2009/002607 patent/WO2009135581A2/en active Application Filing
- 2009-04-08 CA CA2723431A patent/CA2723431C/en active Active
- 2009-04-08 EA EA201001737A patent/EA018920B1/en not_active IP Right Cessation
- 2009-04-08 EA EA201300759A patent/EA201300759A1/en unknown
- 2009-04-08 AU AU2009243812A patent/AU2009243812B2/en not_active Ceased
- 2009-04-08 NZ NZ589691A patent/NZ589691A/en not_active IP Right Cessation
- 2009-04-08 JP JP2011507806A patent/JP5735412B2/en active Active
- 2009-04-08 US US12/991,016 patent/US8546575B2/en active Active
- 2009-04-30 AR ARP090101563A patent/AR072666A1/en unknown
-
2010
- 2010-10-28 IL IL208989A patent/IL208989A/en active IP Right Grant
- 2010-10-29 CO CO10134879A patent/CO6331305A2/en not_active Application Discontinuation
- 2010-12-02 EC EC2010010656A patent/ECSP10010656A/en unknown
- 2010-12-03 ZA ZA2010/08723A patent/ZA201008723B/en unknown
Also Published As
Publication number | Publication date |
---|---|
IL208989A0 (en) | 2011-01-31 |
ES2432383T3 (en) | 2013-12-03 |
EA201300759A1 (en) | 2013-11-29 |
US20110060007A1 (en) | 2011-03-10 |
WO2009135581A2 (en) | 2009-11-12 |
EP2271405A2 (en) | 2011-01-12 |
EP2271405B1 (en) | 2013-07-24 |
IL208989A (en) | 2014-01-30 |
US8546575B2 (en) | 2013-10-01 |
NZ589691A (en) | 2012-11-30 |
JP5735412B2 (en) | 2015-06-17 |
WO2009135581A3 (en) | 2010-08-19 |
AU2009243812A1 (en) | 2009-11-12 |
KR101604366B1 (en) | 2016-03-17 |
CA2723431A1 (en) | 2009-11-12 |
ECSP10010656A (en) | 2011-01-31 |
MX2010011917A (en) | 2010-11-26 |
BRPI0911497B1 (en) | 2021-01-26 |
BRPI0911497A2 (en) | 2019-01-15 |
ZA201008723B (en) | 2012-01-25 |
KR20110004468A (en) | 2011-01-13 |
CO6331305A2 (en) | 2011-10-20 |
WO2009135581A9 (en) | 2010-11-11 |
CN102015026A (en) | 2011-04-13 |
CN102015026B (en) | 2015-11-25 |
BRPI0911497B8 (en) | 2021-05-25 |
EA018920B1 (en) | 2013-11-29 |
EA201001737A1 (en) | 2011-06-30 |
AR072666A1 (en) | 2010-09-15 |
JP2011521907A (en) | 2011-07-28 |
AU2009243812B2 (en) | 2014-06-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2723431C (en) | Nip thiazole derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 | |
EP2247589B1 (en) | 7-azaindole derivatives as selective 11-beta-hydroxysteroid dehydrogenase type 1 inhibitors | |
PT2078001E (en) | Diazepane-acetamide derivatives as selective 11 -hsd1 inhibitors | |
US8486964B2 (en) | Fused pyrrolidino-cyclopropane derivatives as selective 11-beta-hydroxysteroid dehydrogenase type 1 inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request |
Effective date: 20140407 |